Allogeneic Stem Cell Transplantation (Second Edition)

Allogeneic Stem Cell Transplantation

C O N T E M P O R A R Y H E M AT O L O G Y

Judith E. Karp, Series Editor

For other titles published in the series, go to www.springer.com/7861

Allogeneic Stem Cell Transplantation Second Edition

Edited by

Hillard M. Lazarus University Hospitals Case Medical Center Cleveland, OH USA

Mary J. Laughlin Case Western Reserve University Cleveland, OH USA

Editors Hillard M. Lazarus University Hospitals Case Medical Center Cleveland, OH USA [email protected]

Mary J. Laughlin Case Western Reserve University Cleveland, OH USA [email protected]

ISBN 978-1-934115-33-6 e-ISBN 978-1-59745-478-0 DOI 10.1007/978-1-59745-478-0 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2009930362 © Springer Science+Business Media, LLC 2003, 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (www.springer.com)

Dr. Hillard M. Lazarus dedicated his contributions to his wife Joan and his sons Adam and Jeffrey for their unwavering encouragement and support.

Preface

Allogeneic hematopoietic stem cell (HSC) transplantation has undergone fast-paced changes after our original publication of Allogeneic Stem Cell Transplantation: Clinical Research and Practice, first published more than 5 years ago. In this second edition, the editors have focused on topics relevant to evolving knowledge in the field in order to better guide clinicians in decisionmaking and management of their patients, as well as help lead laboratory investigators in new directions emanating from clinical observations. Some of the most respected clinicians and scientists in this discipline have responded in this second edition by providing state-of-the-art discussions addressing these topics. Important advances have been recognized in HLA disparity between HSC donor and recipient triggers for T-cell and NK-cell allorecognition; such may induce the graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects and may cause an engraftment failure. This text covers the scope of human genomic variation, the methods of HLA typing, and interpretation of high-resolution HLA results. Durable GVL responses may be the result of the elimination of leukemia stem cells or the establishment of a durable immune control on their progeny. Alternative sources of donor HSC continue to be used for transplantation at an increased frequency and include HLA-matched unrelated donor and umbilical cord blood; overall patient outcome has improved steadily using these diverse stem cell sources. The administration of reduced-intensity as well as non-myeloablative conditioning has also brought forth new concepts in the management of hematologic malignancies, thought to be of emerging importance in patients with lower grade malignant disorders such as chronic lymphocytic leukemia, multiple myeloma, and low-grade non-Hodgkin lymphoma. The elderly or those with comorbid conditions who have acute leukemia in complete remission also may benefit by using this lower-intensity therapy. The reduced toxicity of these novel conditioning regimens has also raised new possibilities in the application of allogeneic HSC transplantation for patients with non-malignant hematologic disorders such as sickle cell anemia and selected solid tumors such as renal cell carcinoma. Allogeneic SCT remains the only available curative therapy for hematologic malignancies and some inborn errors such as beta-thalassemia. Its application, however, may result in significant morbidity and mortality, predominantly as a consequence of opportunistic infections and GVHD. While differences in HLA between donor and recipient make a crucial contribution to the alloreactivity vii

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driving the donor-mediated GVL response, the cytokine milieu both promotes and regulates the allogeneic response after transplantation. As such, genetic studies correlating donor, host, or the combination of cytokine polymorphisms with disease outcomes have provided useful insight into disease pathogenesis, often confirming effects that have been determined in pre-clinical studies. It is now clear that the polymorphic expression of key cytokines (particularly tumor necrosis factor and interleukin 10) has a demonstrable effect on disease outcome and overall transplant-related mortality. Many challenges in allogeneic SCT remain and include the risk of graft failure, recurrent disease, acute GVHD, opportunistic infections and longterm sequelae such as chronic GVHD, increased risk of second malignancies, endocrinopathies, and iron overload. The editors hope that this new information, well summarized by the authors in this text, will be of significant benefit to clinicians and researchers in allogeneic HSC transplantation. We envision that the generation of further knowledge and clinical studies to be of ultimate benefit to our patients. Cleveland, Ohio, USA

Hillard M. Lazarus, MD Mary J. Laughlin, MD

Contents

  1 Allogeneic Stem Cell Transplantation: The Last Century................ John M. Goldman

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  2 Full Intensity and Reduced Intensity Allogeneic Transplantation in AML.................................................................... Charles Craddock

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  3 Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL)...................................................... Bella Patel, Anthony H. Goldstone, and Adele K. Fielding

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  4 Hematopoietic Progenitor Cell Transplantation for Treatment of Chronic Lymphocytic Leukemia........................... Leslie A. Andritsos, John C. Byrd, and Steven M. Devine

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  5 The Role of Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia Patients in the Era of Tyrosine Kinase Inhibitors............................. Richard T. Maziarz   6 Allogeneic Transplantation for Hodgkin’s Lymphoma.................... William Broderick and Patrick Stiff   7 Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma......................................................... J. Kuruvilla, P. Mollee, and J.H. Lipton

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  8 Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning..................................................................................... 109 Sonali M. Smith and Ginna G. Laport   9 The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults................................................................. 127 Heidi D. Klepin and David D. Hurd

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10 Single Versus Tandem Autologous Hematopoietic Stem Cell Transplant in Multiple Myeloma..................................... 143 David H. Vesole 11 Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma.............................................................. 159 Frank Heinzelmann, Hellmut Ottinge, and Claus Belka 12 The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia............................................................................ 177 Mickey Liao and Gary J. Schiller 13 Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults................................................ 193 David I. Marks 14 Allogeneic Transplantation for Myelodysplastic Syndromes........... 203 Geoffrey L. Uy and John F. DiPersio 15 Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia.................................... 219 Adriana Balduzzi, Lucia Di Maio, Mary Eapen, and Vanderson Rocha 16 Allogeneic Transplantation for the Treatment of Multiple Myeloma........................................................................ 261 Rebecca L. Olin, Dan T. Vogl, and Edward A. Stadtmauer 17 Blood Vs. Marrow Allogeneic Stem Cell Transplantation............... 281 Brian McClune and Daniel Weisdorf 18 Hematopoietic Cell Transplantation from Partially HLA-Mismatched (HLA-Haploidentical) Related Donors.............. 299 Ephraim J. Fuchs and Heather J. Symons 19 Unrelated Donor Transplants............................................................ 345 Andrea Bacigalupo 20 Update on Umbilical Cord Blood Transplantation........................... 363 Karen Ballen 21 Selection of Cord Blood Unit(s) for Transplantation........................ 375 Donna A. Wall and Ka Wah Chan 22 Mobilization of Hematopoietic Cells Prior to Autologous or Allogeneic Transplantation........................................................... 387 Steven M. Devine

Contents 

23 Natural Killer-Cell Based Treatment in Hematopoetic Stem Cell Transplantation................................................................. 413 Martin Stern, Sandrine Meyer-Monard, Uwe Siegler, and Jakob R. Passweg 24 Cryopreservation of Allogeneic Stem Cell Products........................ 427 Noelle V. Frey and Steven C. Goldstein 25 Concepts and Controversies in the Use of Novel Preparative Regimens for Allogeneic Stem Cell Transplantation....................... 441 Steven C. Goldstein and Selina Luger 26 Allogeneic Haematopoietic Stem Cell Transplantation and Natural Killer Cell Alloreactivity............................................... 459 Franco Aversa and Andrea Velardi 27 Therapeutic Potential of Mesenchymal Stem Cells in Hematopoietic Stem Cell Transplantation........................... 477 Luis A. Solchaga and Hillard M. Lazarus 28 Hematopoietic Stem Cell Transplantation for Thalassemia............. 491 Javid Gaziev and Guido Lucarelli 29 Viral Infections in Hematopoietic Stem Cell Transplant Recipients.......................................................................................... 505 Per Ljungman 30 Fungal Infections.............................................................................. 533 John R. Wingard 31 Immune Reconstitution and Implications for Immunotherapy Following Hematopoeitic Stem Cell Transplantation....................... 545 Kirsten M. Williams and Ronald E. Gress 32 Acute Graft Versus Host Disease: Prophylaxis................................. 565 Corey Cutler, Vincent T. Ho, and Joseph H. Antin 33 Chronic Graft-Versus-Host Disease.................................................. 577 Madan Jagasia and Steven Pavletic 34 Post-transplant Lymphoproliferative Disorder.................................. 597 Ran Reshef, Alicia K. Morgans, and Donald E. Tsai 35 Psychological Care of Adult Allogeneic Transplant Patients........... 619 Flora Hoodin, Felicity W.K. Harper, and Donna M. Posluszny 36 Second Allogeneic Transplantation: Outcomes and Indications.................................................................................. 657 Koen van Besien, Dan Pollyea, and Andrew Artz

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37 Minimal Residual Disease................................................................ 667 Mehmet Uzunel 38 Functional Assessment Tools and Co-morbidity Scoring in Hematopoietic Progenitor Cell Transplantation........................... 687 Sergio Giralt and Uday Popat 39 Unique Thrombotic and Hemostatic Complications Associated with Allogeneic Hematopoietic Stem Cell Transplantation................................................................. 695 Amber A. Petrolla, Hillard M. Lazarus, and Alvin H. Schmaier 40 How Much Isolation Is Enough for Allografts?................................ 717 Brandon Hayes-Lattin 41 Monoclonal Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies............... 733 Maria Corinna Palanca-Wessels and Oliver Press 42 Treatment of Acute Graft-vs-Host Disease....................................... 747 Steven C. Goldstein, Sophie D. Stein, and David L. Porter 43 The Importance of Non-Human Primate Models for Pre-clinical Studies in Hematopoiesis......................................... 767 Erzsebet Szilagyi, Nadim Mahmud, and Amelia Bartholomew 44 In Vivo Models of Allogeneic Hematopoietic Stem Cell Transplantation.................................................................................. 789 Lisbeth A. Welniak and William J. Murphy 45 Dendritic Cells.................................................................................. 807 Jacalyn Rosenblatt and David Avigan 46 Augmentation of Hematopoietic Stem Cell Transplantation with Anti-cancer Vaccines................................................................ 855 Edward D. Ball and Peter R. Holman Erratum ................................................................................................... .

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Index......................................................................................................... 871

Contributors

Leslie A. Andritsos, MD Division of Hematology & Oncology, The Ohio State University Medical Center, Columbus, OH, USA Joseph H. Antin, MD Harvard Medical School and Dana Farber Cancer Institute, Boston, MA, USA Andrew Artz, MS, MD Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA Franco Aversa, MD Section of Haematology and Clinical Immunology, Department of Clinical and Experimental Medicine, HSCT Unit, University of Perugia, Perugia, Italy David Avigan, MD Division of Hematological Malignancies/Bone Marrow Transplantation, Beth Israel Deaconess Medical Center, Boston, MA, USA Andrea Bacigalupo Ospedale San Martino, Genova, Italy Adriana Balduzzi, MD Hematopoeitic Transplant Unit, Clinica Pediatrica, Università degli Studi di Milano, Bicocca Ospedale, San Gerardo, Italy Edward D. Ball, MD Division of Blood and Marrow Transplantation, Department of Medicine and the Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA, USA Karen Ballen, MD Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA Amelia Bartholomew, MD Division of Transplant Surgery, Department of Surgery, University of Illinois at Chicago College of Medicine, Chicago, IL, USA

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Claus Belka, MD Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany William Broderick, MD Division of Hematology-Oncology, Department of Medicine, Bone Marrow Transplant Program, Loyola University Stritch School of Medicine, Maywood, IL, USA John C. Byrd, MD Division of Hematology & Oncology, The Ohio State University Medical Center, Columbus, OH, USA Ka Wah Chan, MD Pediatric Blood and Marrow Transplantation Program, Texas Transplant Institute, San Antonio, TX, USA Charles Craddock Centre for Clinical Haematology, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK Corey Cutler, MD, MPH, FRCP Harvard Medical School and Dana Farber Cancer Institute, Boston, MA, USA Steven M. Devine, MD Division of Hematology & Oncology, The Ohio State University Medical Center, Columbus, OH, USA Lucia Di Maio, MD Hematopoeitic Transplant Unit, Clinica Pediatrica, Università degli Studi di Milano, Bicocca Ospedale, San Gerardo, Italy John F. DiPersio, MD, PhD. Section of BMT and Leukemia, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA Mary Eapen, MD Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA Adele K. Fielding, MD Department of Haematology, Royal Free and University College Medical School, London, UK Noelle V. Frey, MD Division of Hematology-Oncology and Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PA, USA Ephraim J. Fuchs, MD Divisions of Pediatric Oncology, Cancer Immunology and Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA Javid Gaziev, MD International Centre for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Rome, Italy

Contributors 

Sergio Giralt, MD Department of Stem Cell Transplant and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA John M. Goldman, MD Department of Hematology, Imperial College Faculty of Medicine and World Marrow Donor Association, London, UK Steven C. Goldstein, MD Division of Hematology-Oncology and Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PA, USA Anthony H. Goldstone Department of Haematology, University College London Hospitals, London, UK Ronald E. Gress, MD Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Felicity W.K. Harper, PhD Communication and Behavioral Oncology Program, Barbara Ann Karmanos Cancer Institute and Department of Family Medicine and Public Health Sciences, Wayne State University School of Medicine, Detroit, MI, USA Brandon Hayes-Lattin, MD Center for Hematologic Malignancies, OHSU Cancer Institute, Oregon Health and Science University, Portland, OR, USA Frank Heinzelmann, MD Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany Vincent T. Ho, MD Harvard Medical School and Dana Farber Cancer Institute, Boston, MA, USA Peter R. Holman, MD Division of Blood and Marrow Transplantation, Department of Medicine and The Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA, USA Flora Hoodin, PhD Department of Psychology, Eastern Michigan University, Ypsilanti, MI, USA David D. Hurd, MD Section of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC, USA Madan Jagasia, MBBS, MS Division of Hematology-Oncology, Department of Medicine, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA Heidi D. Klepin, MD Section of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, NC, USA

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Contributors

John Kuruvilla, MD Division of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, Toronto, ON, Canada Ginna G. Laport, MD Division of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA, USA Hillard M. Lazarus, MD Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA Mickey Liao, MD Hematologic Malignancies Unit/Stem Cell Transplant Unit, University of California at Los Angeles, Los Angeles, CA, USA Jeffrey H. Lipton, MD Division of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, Toronto, ON, Canada Per Ljungman, MD Department of Hematology, Karolinska University Hospital, Stockholm, Sweden Guido Lucarelli, MD International Centre for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Rome, Italy Selina Luger, MD Division of Hematology-Oncology and Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PA, USA Nadim Mahmud, MD, PhD Division of Hematology-Oncology, University of Illinois at Chicago, Chicago, IL, USA David I. Marks, MD University Hospitals of Bristol, Oncology Day Beds, Bristol Children’s Hospital, Bristol, UK Richard T. Maziarz, MD Center for Hematologic Malignancies, Adult Bone Marrow Transplantation Program, Oregon Health Science Cancer Institute, Oregon Health & Science University, Portland, OR, USA Brian McClune, DO Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, MN, USA Keith McCrae, MD Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA Sandrine Meyer-Monard, MD Division of Hematology, Basel University Hospital, Basel, Switzerland

Contributors 

Peter Mollee, MD Department of Haematology, Princess Alexandra Hospital and University of Queensland, Brisbane, QLD, Australia Alicia K. Morgans, MD Abramson Cancer Center, Hematologic Malignancies Program, University of Pennsylvania Medical Center, Philadelphia, PA, USA William J. Murphy, MD Department of Dermatology, University of California, Davis Sacramento, CA 95817 Rebecca L. Olin, MD Abramson Cancer Center, Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Hellmut Ottinger, MD Department of Bone Marrow Transplantation, University of Essen, Essen, Germany Maria Corinna Palanca-Wessels, MD Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA, USA Jakob R. Passweg, MD Division of Hematology, Geneva University Hospitals, Geneva, Switzerland Bella Patel Department of Haematology, Royal Free and University College Medical School, London, UK Steven Pavletic, MD Graft-versus-Host and Autoimmunity Unit, Experimental Transplantation and Autoimmunity Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Amber A. Petrolla, MD Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Group, Cleveland, OH, USA Dan Pollyea, MD Divisions of Hematology and Oncology, Stanford University School of Medicine, Palo Alto, CA, USA Uday Popat, MD Department of Stem Cell Transplant and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA David L. Porter, MD Allogeneic Stem Cell Transplantation, University of Pennsylvania Medical Center, Philadelphia, PA, USA Donna M. Posluszny, PhD Department of Medicine, University of Pittsburgh School of Medicine and Behavioral Medicine Clinical Service, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

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Contributors

Oliver W. Press, MD Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle, WA, USA Ran Reshef, MD Abramson Cancer Center, Hematologic Malignancies Program, University of Pennsylvania Medical Center, Philadelphia, PA, USA Vanderson Rocha, MD, PhD Acute Leukemia Working Party of the European Blood and Marrow Transplant Group, Hopital Saint Antoine and Hematopoeitic Transplant Unit and Eurocord Registry, Hopital Saint Louis, Assistance Publique des Hopitaux de Paris, University of Paris, Paris, France Jacalyn Rosenblatt, MD Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA Gary J. Schiller, MD Hematologic Malignancies Unit/Stem Cell Transplant Unit, University of California at Los Angeles, Los Angeles, CA, USA Alvin H. Schmaier, MD Division of Hematology and Oncology, Case Western Reserve University and University Hospital Case Medical Group, Cleveland, OH, USA Uwe Siegler, MD Division of Hematology, Basel University Hospital, Basel, Switzerland Sonali M. Smith, MD Section of Hematology/Oncology, The University of Chicago Medical Center, Chicago, IL, USA Luis A. Solchaga, PhD Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA Edward A. Stadtmauer, MD Abramson Cancer Center, Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Sophie D. Stein, MD Department of Hematology-Oncology, University of Pennsylvania Medical Center, Philadelphia, PA, USA Martin Stern, MD Division of Hematology, Basel University Hospital, Basel, Switzerland Patrick Stiff, MD Division of Hematology-Oncology, Department of Medicine, Bone Marrow Transplant Program, Loyola University Stritch School of Medicine, Maywood, IL, USA Heather J. Symons, MD Divisions of Pediatric Oncology, Cancer Immunology and Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Contributors 

Erzsebet Szilagyi, MD Division of Hematology-Oncology, University of Illinois at Chicago, Chicago, IL, USA Donald E. Tsai, MD Abramson Cancer Center, Hematologic Malignancies Program, University of Pennsylvania Medical Center, Philadelphia, PA, USA Geoffrey L. Uy, MD Section of BMT and Leukemia, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA Mehmet Uzunel, PhD Karolinska University Hospital, Stockholm, Sweden Koen van Besien, MD Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA Andrea Velardi, MD Section of Haematology and Clinical Immunology, HSCT Unit, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy David H. Vesole, MD, PhD, FACP Attending Physician, St. Vincent’s Comprehensive Cancer Center, New York, NY, USA Dan T. Vogl, MD Abramson Cancer Center, Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Donna A. Wall, MD Cancer Care Manitoba, Winnipeg, MB, Canada Daniel Weisdorf, MD Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, MN, USA Lisbeth Welniak, PhD Department of Dermatology, University of California, Davis Sacramento, CA 95817 Kirsten M. Williams, MD Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA John R. Wingard, MD Division of Hematology-Oncology, Bone Marrow Transplant Program, University of Florida Shands Cancer Center, Gainesville, FL, USA

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Chapter 1 Allogeneic Stem Cell Transplantation: The Last Century John M. Goldman

Sporadic and always unsuccessful attempts to reconstitute bone marrow function by transfusion of blood, bone marrow or fetal liver cells collected from normal individuals were made in the nineteenth and first half of the twentieth centuries, but in practice the notion that hematopoietic stem cell transplantation could prove to be of clinical value proceeded only slowly in the last century [1]. One of the earlier important observations was made by a Dutch scientist in 1922, who noted that the expected thrombocytopenia and hemorrhage in guinea pigs following total body irradiation (TBI) could be prevented by shielding from irradiation the animal’s legs [2]. The studies were not pursued at that time, but in 1949, Jacobson and colleagues reported that mice exposed to lethal doses of irradiation could be protected by shielding the spleen, which functions as a hematopoietic organ in the mouse [3]. These workers went on to show that this protection could also be provided by transfusion of spleen cells into the mouse peritoneum [4]. In the same year, Lorenz and coworkers showed that “lethally” irradiated mice and guinea pigs could be protected by intravenous injections of bone marrow cells collected from syngeneic animals [5]. One possible interpretation of these findings was simply that a humoral factor transferred from the healthy animal was able to “stimulate regeneration” of hematopoiesis in the irradiated animal, but experiments using a variety of histochemical and genetic markers showed convincingly that this prevention of lethality after irradiation was due to transfer of donor cells rather than of components of the plasma [6–9]. In 1956, Ford introduced the term “radiation chimaera” to describe an animal whose hematopoiesis was derived from a donor animal after TBI [8]. Subsequently, it was shown that such chimerism could be established in animals whose own hematopoiesis was destroyed by combinations of cytotoxic drugs without any irradiation. Also, in 1956, Barnes and colleagues studied a lymphoid leukemia that could be transmitted in mice by passage of cells intravenously or subcutaneously [10, 11]; when these leukemic mice were subjected to 1,500 rad of TBI followed by transfusion of cells from a normal donor animal, the majority survived. This was the first convincing demonstration that leukemia cells could be killed by high dose irradiation and laid the foundation for the use of high dose cytotoxic drugs

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_1, © Springer Science + Business Media, LLC 2003, 2010

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treatment (with or without irradiation) followed by marrow infusion as therapy for leukemia in man.

1.  Early Clinical Studies Some of the earliest interpretable studies of stem cell transplantation in man involved autografting. In 1958, Kurnick and colleagues collected and cryopreserved bone marrow cells from two patients with metastatic malignant disease; the patients were then treated with high dose irradiation and their thawed marrow cells were infused intravenously [12]. Though the authors could not be certain that the subsequent marrow recovery was indisputably due to the autologous infusion of marrow cells, this seemed very probable. The following year Thomas and coworkers reported the results of treating two patients with acute leukemia, both of whom had identical twins, by high dose irradiation followed by transfusion of nucleated cells from their respective twins [13]. Both patients engrafted but in both cases the leukemia recurred and was the cause of death. Also, in 1959, Mathé reported the results of his attempts to treat six persons accidentally exposed to high dose irradiation in Vinca in Yugoslavia [14]; there was transient evidence of engraftment in some of the patients. Subsequently, his group in Paris reported the first case of complete engraftment with survival beyond 1 year; in the event the patient developed both acute and chronic graft-versus-host disease (GvHD) and died eventually of varicella encephalitis [15]. In 1968, Mathé summarized his experience in treating 21 patients by bone marrow transplantation, of which 6 had failed to engraft and 8 had sustained GvHD [16]. The first truly successful use of allogeneic hematopoietic cells in man was reported by Gatti and coworkers from Minneapolis in 1968 [17]. They treated a five-month-old male with a sexlinked lymphopenic immunological deficiency by transfusion of cells from blood buffy coat and bone marrow collected from an immunologically competent sibling donor. The patient was clinically well and the continued success of the procedure was confirmed by a follow-up report published 25 years later [18]. This was apparently the first patient cured by infusion of hematopoietic cells collected from an allogeneic donor, using of course contemporary HLA matching techniques. The first successful allograft for aplastic anemia was reported by Thomas and coworkers in 1972 [19]. In 1975, the status of syngeneic and allogeneic transplantation in man was well summarized by a two-part review published by Thomas and coworkers in the New England Journal of Medicine [20]. Techniques for conditioning the individual patient were discussed and methodology for collecting and transplanting bone marrow cells was described in detail. The experience with transplants performed for 37 patients with aplastic anemia and 73 patients with leukemia was summarized. Attention was drawn to the problems of GvHD, slow engraftment and opportunistic infection. This was followed by the first definitive paper describing the use of allogeneic stem cell transplantation to treat a large series of patients with “end-stage” acute leukemia in Seattle [21]; Thomas and colleagues reported that of 100 poor-risk patients, 13 had become very long-term leukemia-free survivors. It was clear that the risk of transplant-related mortality was substantial and some of those who survived the procedure relapsed with leukemia, but the notion that even a minority of

Chapter 1  Allogeneic Stem Cell Transplantation: The Last Century 

these poor-risk patients might be cured was seen by many as “exciting.” The workers reasoned that if some patients with advanced leukemia could be cured by allografting, the incidence of cure might be considerably higher if the transplants were performed in complete remission. This assumption proved subsequently to be correct.

2.  Allografting for Aplastic Anemia The first systematic approach to the use of allogeneic stem cell transplantation started in Seattle in the early 1970s. By 1974, the group was able to report results of transplanting 38 patients with aplastic anemia, most of whom had been conditioned with cyclophosphamide 50  mg/kg daily for 4  days [22], which was a modification of a regimen proposed originally by Santos in 1970. One major problem with these early transplants for aplastic anemia was failure of sustained engraftment, which was attributed to sensitization of the host to minor histocompatibility antigens present on donor cells. This could be overcome to some extent by increasing the intensity of the conditioning. In 1976, Camitta reported results of a randomized prospective study showing that allogeneic stem cell transplantation resulted in survival superior to that achieved with conventional nontransplant therapy [23].

3.  Allografting for Acute Leukemia In 1979, the Seattle group was able to report preliminary data on results of allogeneic stem cell transplant using HLA-identical siblings for 19 patients with “acute nonlymphoblastic leukemia” in remission [24]. A follow-up paper 4  years later reported that 10 of the first 19 patients were alive and free of leukemia at more than 5 years after their transplants [25]. These results led specialist groups on both sides of the Atlantic to initiate programs for transplanting adult patients with both acute myeloid and acute lymphoblastic leukemia (ALL) in remission. Clearly, children with ALL in first remission continued to be candidates for maintenance chemotherapy rather than allografting, but the notion of offering a transplant to a child in second remission of ALL gained support. A further important step in the use of allogeneic SCT for acute leukemia was the first successful use of an unrelated donor – as reported by Hansen and colleagues in 1980 [26]. Since that time it has been generally accepted that the best donor for a given patient is an HLA-matched sibling (or possibly a genetically identical twin), but HLA matched volunteer donors can in some series yield clinical results comparable to those achieved with sibling donors. For children cord blood stem cells, as originally demonstrated in 1988 by Gluckman and coworkers in Paris [27], have become an important alternative source of stem cells, in the absence of a matched sibling. The extent to which cells in the graft is depleted played an important role in control and eradication of leukemia was a matter of considerable debate in the 1970s. In the late 1979 and 1981, the Seattle group published two important papers that showed convincingly that relapse of acute leukemia was much rarer in patients who sustained acute or chronic GvHD compared with those who had little or no GvHD [28, 29]. This was impressive if indirect evidence that a

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graft-versus-leukemia (GvL) effect which segregated with a GvHD effect was important in suppressing or eradicating leukemia at least in some cases. The later demonstration that depletion of T-cells from the donor inoculum increased the incidence of leukemia relapse, most especially in chronic myeloid leukemia (CML) [30, 31], helped to establish the concept that a GvL effect did indeed play a crucial role in the cure of leukemia by allogeneic SCT. Final proof of the efficacy of the GvL effect came from the observation by Kolb and coworkers that relapse after allogeneic stem cell transplantation for CML could be readily reversed by transfusion of lymphocytes of donor origin [32].

4.  Allografting for Chronic Myeloid Leukemia It is difficult in the modern era to imagine that CML was generally regarded until the 1980s as an inexorably fatal disease for which no cure could usefully be contemplated. It was therefore very exciting when in 1979, Fefer and co­workers in Seattle published a report of four patients with CML in chronic phase that had been treated with high dose chemoradiotherapy followed by transplantation of marrow cells collected from their respective identical twins [33]. All four patients were well without evidence of Ph-positive marrow metaphases at follow-up periods from 22 to 31 months after transplantation. Though it was entirely possible that each of these patients would still relapse, it gave impetus to the notion that allogeneic stem cell transplantation performed with marrow cells from HLA-identical siblings might be a useful approach to managing and hopefully curing this form of leukemia. Transplant programs for CML using matched sibling donors were therefore initiated in Seattle and elsewhere [34–36]. Preliminary results with small numbers of patients confirmed that the principal risks were indeed GvHD and opportunistic infection, whereas relapse was rare in survivors. In the early 1980s, Prentice and colleagues in London showed that depletion of donor marrow cells by incubation with anti-T cells monoclonal antibodies prior to infusion to the patient very greatly reduced the incidence of GvHD [37]. Unfortunately, T-cell depletion was associated with an increased risk of nonengraftment and impaired immune reconstitution. It appeared also to abrogate the GvL effect, most prominently in CML, since the actuarial relapse for CML patients allografted in chronic phase who received sibling marrow cells treated with a pan-lymphoid monoclonal antibody (CD52, Campath, now known as alemtuzumab) approached 70%. Various methods of T-cell depletion have been explored subsequently and its use is undoubtedly valuable in selected cases, most especially where later relapse of leukemia is amenable to management with donor lymphocyte infusions.

5.  Graft-Versus-Host Disease In the 1950s, Barnes and Loutit reported that irradiated mice that received spleen cells from syngeneic donors engrafted and survived without significant problems, whereas irradiated mice transfused with spleen cells from a different murine strain died within 100 days of the transplant [38]. These observations were extended by Cohen and coworkers who noted that the affected animals had severe diarrhea, weight loss and skin lesions, and a syndrome that they

Chapter 1  Allogeneic Stem Cell Transplantation: The Last Century 

designated “secondary disease” [39]. Gradually it became clear that this secondary disease was probably caused by immunological incompatibility between donor lymphoid cells and specific organs in the recipient, a syndrome now designated “graft-versus-host disease.” The requirements for establishment of GvHD are: (1) that the graft consists of immunologically competent cells; (2) that the host cells express antigens that are absent on the donor cells; and (3) that the recipient is incapable of mounting an effective immunological reaction against the graft. The requirements can, of course, be met in patients who have not been subjected to conditioning prior to transplant, for example in the patient with severe combined immunodeficiency or the patient who has received extensive chemotherapy for Hodgkins’s disease. It is conventional today to ensure that all blood products administered to patients post transplant are irradiated in vitro to at least to 1,500 cGy to prevent allogeneic GvHD.

6.  Histocompatibility In the late 1930s, Gorer described alloantigens in the sera of mice which comprise part of a murine major histocompatibility complex (MHC), subsequently named H2. These alloantigens were shown to play a central role in tissue rejection [40, 41]. In 1958, Dausset described the first analogous human antigen, then named Mac and now known as HLA-A2 [42]. A number of scientific workshops were then convened at regular intervals and by 1968, it had become clear that human leukocyte antigens (HLA) A and B were closely linked on the short arm of human chromosome 6. HLA-C was identified in 1971. The HLA D locus which is defined in part by expression of alloreactivity in the mixed lymphocyte culture was characterized by Dupont in 1980 [43]. The term haplotype was introduced to describe a sequence of genes on one or other chromosome 6 that together comprise the major MHC in man [44]. In more recent years restriction fragment length polymorphisms were used to characterize more precisely the various HLA genes and this technique has, in turn, given way to a variety of molecular methods, which include direct sequencing of polymorphic regions and allele specific oligonucleotide PCR (Table 1-1).

7.  Evolution of Conditioning Regimens Therapeutic regimens were developed originally as immunosuppression to permit engraftment in patients with nonmalignant conditions (i.e., genetic diseases or aplastic anemia) and were at the time termed “conditioning regimens.” When the use of allogeneic stem cell transplantation was adapted for patients with leukemia, the regimen was intended to provide immunosuppression but also to eradicate residual leukemia cells, yet the term “conditioning regimen” was retained. Initially, the Seattle group concentrated on the use of TBI delivered from two opposing 60Cobalt sources while Santos in Baltimore performed transplants after administration of high dose cyclophosphamide. Because the leukemia relapse rate was relatively high with both approaches to conditioning, both were changed. The Seattle group adopted the regimen of high dose cyclophosphamide followed by 1,000 cGy of TBI (cyclo-TBI); initially the TBI was administered as a single dose but subsequently it was given as fractions over three consecutive days. Later, the use of gamma irradiation

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J.M. Goldman Table 1-1.  Chronology of selected important developments in hematopoietic stem cell transplantation in the last century. 1930s   Gorer lays the foundation for the major histocompatibility complex in mice 1950s   Description of the first “transplantation antigen” in man   Description of secondary disease, later termed “graft-versus-host disease” 1960s   Identification of the major histocompatibility complex in man   Syngeneic transplants for AA   Allografts for immune deficiency diseases 1970s   Technology refined for performed human stem cell allografts   SD allo-SCT to treatment AML in relapse   SD allo-SCT to treat AML in remission   SD-allo-SCT to treat CML in advanced phase   Syngeneic transplants to treat CML in chronic phase   Establishment of the first volunteer donor panel 1980s   Allo-SCT to treat CML in chronic phase   MUD-SCT to treat acute leukemia   Recognition that hematopoietic stem cells were present in the peripheral blood   Introduction of T-cell depletion with monoclonal antibodies   Identification of umbilical cord as source of hematopoietic stem cells 1990s   Demonstration of the efficacy of DLI, most notably in CML   First use of G-CSF to mobilize stem cell from peripheral blood   Introduction of reduced intensity conditioning allo-SCT (mini-transplants) SCT stem cell transplantation, AA aplastic anemia, AML acute myeloid leukemia, CML chronic myeloid leukemia, SD sibling donor, MUD matched unrelated donor, DLI donor lymphocyte infusions, G-CSF granulocyte colony-stimulating factor

was replaced by X-rays from a linear accelerator. Meanwhile the Baltimore group designed a combination of high dose busulfan with cyclophosphamide (BuCy) and despite many modifications tested subsequently by specialist groups on both sides of the Atlantic, most conditioning regimens for leukemia today still comprise either “cyclo-TBI” or “BuCy.”

8.  Donor Selection It is interesting to note that the progression in the choice of donors for the different diseases treated by allogeneic transplantation over the years has followed essentially the same sequence. Thus with some exceptions the first success was achieved with syngeneic donors, and this, in turn, set the scene

Chapter 1  Allogeneic Stem Cell Transplantation: The Last Century 

for studies with genetically HLA-identical sibling donors. It was for some while believed that human hematopoietic stem cell transplants could not be successful without this level of matching, but it appeared subsequently that one or even two antigens HLA mismatched family members could be used as transplant donors. The observation that matched unrelated donors could also be used with success (mentioned above) prepared the way for establishment of unrelated donor registries worldwide, such that today more than 13 million volunteers have been tissue typed with varying levels of resolution, each of whom could theoretically serve as a hematopoietic stem cell donor. Hematopoietic stem cells with marrow regenerating capacity can be collected either from the marrow or from the peripheral blood of selected donors. Cord blood stem cells are also valuable as source of stem cells in children and are now being used with increasing success also for adult patients. The use of stem cell transplantation has developed far over the last 40 years. There is every hope that this pace of development will be maintained, such that transplant-related mortality may fall below its current level and transplants may safely be offered on a more routine basis to patients with both malignant and nonmalignant conditions.

References   1. Santos GW (1983) History of bone marrow transplantation. Clin Haematol 12:611–639   2. Fabricius-Moeller J (1922) Experimental studies of hemorrhagic diathesis from X-ray sickness. Levin and Munksgaard, Copenhagen   3. Jacobson LO, Marks EK, Gaston EO, Zirkle RE (1949) Effect of spleen protection on mortality following X-irradiation. J Lab Clin Med 34:1538–1543   4. Jacobson LO, Simmons EL, Marks EK, Eldredge JH (1951) Recovery from irradiation injury. Science 113:510–511   5. Lorenz E, Uphoff DE, Reid TR, Shelton E (1951) Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Nat Cancer Inst 12:197–201   6. Lindsley DL, Odell TT, Tausche FG (1955) Implantation of functional erythropoietic elements following total body irradiation. Proc Soc Exp Biol Med 90:512–515   7. Nowell PC, Cells LJ, Habermeyer JG, Roan PL (1956) Growth and continued function of rat marrow cells in X-irradiated mice. Cancer Res 16:256–261   8. Ford CE, Hamerton JL, Barnes DWH, Loutit JF (1956) Cytological identification of radiation chimaeras. Nature 177:452–454   9. Mitchison NA (1956) The colonisation of irradiated tissue by transplanted spleen cells. Br J Exp Pathol 37:239–247 10. Barnes DWH, Corp MJ, Loutit JL et  al (1956) Treatment of murine leukaemias with x-rays and homologous bone marrow. Br Med J 2:626–627 11. Barnes DWH, Loutit JF (1957) Treatment of murine leukaemia with X-rays and homologous bone marrow. II. Br Med J 3:241–252 12. Kurnick NB, Montano A, Gerdes JC et al (1958) Preliminary observations on the treatment of postirradiation hematopoietic depression in man by the infusion of stored autogenous bone marrow. Ann Intern Med 49:973–986 13. Thomas ED, Lochte HL Jr, Cannon JH et al (1959) Supralethal whole body irradiation and isologous marrow transplantation in man. J Clin Invest 38:1709–1716 14. Mathé G, Amiel JL, Schwarzenberg L et al (1963) Hematopoietic chimera in man after allogeneic (homologous) bone marrow transplantation. BMJ 2:1633–1635 15. Mathé G, Jammet H, Pendic B et  al (1967) Transfusions et greffes de moelle osseuse homologue chez des humains irradiés à haute dose accidentellement. Rev Fr Etud Clin Biol 4:226–238

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J.M. Goldman 16. Mathé G (1968) Bone marrow transplantation. In: Rappaport FT, Dausset J (eds) transplantation. Grune and Stratton, New York, pp 284–303 17. Gatti RA, Meuwissen HJ, Allen HD (1968) Immunological reconstitution of sexlinked lymphopenic immunological deficiency. Lancet ii:1366–1369 18. Bortin MM, Bach FH, van Bekkum DW, Good RA, van Rood JJ (1994) 25th anniversary of the first successful bone marrow transplants. Blood 73:603–613 19. Thomas ED, Buckner CD, Storb R et al (1972) Aplastic anemia treated by marrow transplantation. Lancet 1:284–289 20. Thomas ED, Storb R, Clift RA et al (1975) Bone marrow transplantation. N Engl J Med 292:832–843 895–902 21. Thomas ED, Buckner CD, Banaji M et al (1977) One-hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49:511–533 22. Storb R, Thomas ED, Buckner CD et  al (1974) Allogeneic marrow grafting for treatment for aplastic anemia. Blood 43:157–180 23. Camitta BM, Thomas ED, Nathan DG et  al (1957) Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 48:63–70 24. Thomas ED, Buckner CD, Clift RA et al (1979) Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med 301:597–599 25. Thomas ED (1983) Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med 309:1539 (letter) 26. Hansen JA, Cift RA, Thomas ED et al (1980) Transplantation of marrow from an unrelated donor to a patient with acute leukaemia. N Engl J Med 303:565–567 27. Gluckman E, Broxmeyer HE, Auerbach AD et al (1989) Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLAidentical sibling. N Engl J Med 321:1174–1178 28. Weiden PL, Flournoy N, Thomas ED et  al (1979) Antileukemic effect of graftversus-host disease in human recipients of allogeneic grafts. N Engl J Med 300:1068–1073 29. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED (1981) Antileukemic effect of chronic graft-versus-host disease : contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 304:1529–1533 30. Apperley JF, Jones L, Hale G et al (1986) Bone marrow transplantation for chronic myeloid leukaemia: T-cell depletion reduces the risk of graft-versus-host disease but may increase the risk of leukaemic relapse. Bone Marrow Transplant 1:53–66 31. Goldman JM, Gale RP, Horowitz MM et al (1988) Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: increased risk of relapse associated with T-cell depletion. Ann Intern Med 108:806–814 32. Kolb HJ, Mittermuller J, Clemm CH et  al (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465 33. Fefer A, Cheever MA, Thomas ED et al (1979) Disappearance of the Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin. N Engl J Med 300:333–337 34. Clift RA, Buckner CD, Thomas ED et al (1982) Treatment of chronic granulocytic leukaemia in chronic phase by allogeneic marrow transplantation. Lancet 2:621–623 35. Goldman JM, Baughan ASJ, McCarthy DM, Worsley AM et  al (1982) Marrow transplantation for patients in the chronic phase of chronic granulocytic leukaemia. Lancet 2:623–625 36. McGlave PB, Arthur DC, Kim TH et al (1982) Successful allogeneic bone-marrow transplantation for patients in the accelerated phase of chronic granulocytic leukaemia. Lancet 2:625–627

Chapter 1  Allogeneic Stem Cell Transplantation: The Last Century  37. Prentice HG, Blacklock HA, Janossy G et al (1984) Depletion of T lymphocytes in donor marrow prevents significant graft-versus-host disease in matched allogeneic leukaemic marrow transplant recipients. Lancet 1:472–476 38. Barnes DWH, Loutit JF (1955) Spleen protection: the cellular hypothesis. In: Bacq ZM (ed) Radiobiology Symposium Liege. Butterworths, London, pp 134–135 39. Cohen JA, Vos O, van Bekkum DW (1957) The present status of radiation protection by chemical and biological agents in mammals. In: de Hevesy GC, Forssberg AG, Abbott JD (eds) Advances in Radiobiology. Oliver & Boyd, Edinburgh, pp 134–144 40. Gorer RA (1936) The detection of antigenic differences in mouse erythrocytes by the employment of immune sera. Br J Exp Pathol 17:42–50 41. Gorer RA (1937) The genetic and antigenic basis of tumour transplantation. J Pathol Bacteriol 44:691–697 42. Dausset J (1958) Iso-leuko-anticorps. Acta Haematol 20:156–166 43. Dupont B (1980) HLA factors and bone marrow grafting. In: Burchenal JH, Oettgen HF (eds) Cancer: achievements, challenges and prospects for the 1980s. Grune & Stratton, New York, pp 683–693 44. Ceppellini R, van Rood JJ (1974) The HLA system. I. Genetic and molecular biology. Semin Hematol 11:233–251

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Chapter 2 Full Intensity and Reduced Intensity Allogeneic Transplantation in AML Charles Craddock

1.  Introduction Acute myeloid leukemia (AML) is now the commonest indication for allogeneic stem cell transplantation (SCT) in adults [1]. This reflects the continued inability of conventional chemotherapeutic regimens to deliver long-term disease-free survival in most adults -- a failure which is particularly marked in patients over the age of 50 years whose outcome has barely improved in the last three decades [2, 3]. Whilst it has been clear for a number of years that the allogeneic transplantation delivers a more potent anti-leukemic effect than chemotherapy, the toxicity of myeloablative conditioning regimens has precluded its use in precisely the group of patients who urgently need new therapeutic options. However, the recent demonstration that the use of reduced intensity conditioning regimens substantially reduces the transplant-related mortality (TRM) has provided the prospect of delivering a potentially curative graft-versus-leukemia (GVL) effect in patients in whom it was previously contraindicated [4, 5]. Importantly, this has provided a new treatment option for a group of patients whose outcome if treated with chemotherapy alone would be very poor.

2.  Biology of AML and Impact on Future Development of Therapeutic Strategies in AML The demonstration that AML originates from a population of mitotically quiescent leukemic stem cells (LSC) is likely to transform treatment strategies in the coming decade [6]. Since the markedly reduced sensitivity of LSC to a number of currently used chemotherapeutic agents is likely to underlie the high rate of disease relapse in AML, there is an urgent need to develop distinct therapeutic approaches which target this cellular compartment. The notable clinical activity of the tyrosine kinase inhibitor, imatinib, in patients with chronic myeloid leukemia (CML) led to a initial enthusiasm that targeted inhibition of dysregulated signaling pathways might be effective in AML [7]. However, this was not substantiated by the initial experience with drugs From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_2, © Springer Science + Business Media, LLC 2003,2010

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designed to inhibit constitutively active FLT3 and Ras pathways, and clinical responses to these agents in AML are rare and usually of short duration [8–10]. Furthermore, it is now clear from cytogenetic analysis and, more recently from microarray studies that AML is a highly heterogeneous disease at a molecular level whose pathogenesis is dependent on the acquisition of mutations in a number of different cellular pathways [11, 12]. This model is supported by data from transgeneic mouse models which demonstrate that mutations in at least two distinct cellular pathways are required for the pathogenesis of AML [13, 14]. As a consequence, it appears unlikely that a pharmacological strategy which targets a single dysregulated pathway will be of sustained therapeutic benefit. Attention is instead switching to the development of agents which can target the LSC and approaches are under investigation that include inhibitors of pathways mediating self-renewal and proliferation, such as NFkB, Wnt, and hox genes [15–17]. 2.1.  Emergence of Immunotherapeutic Strategies as an Important form of Targeted Therapy The challenges associated with the development of new drug therapies in AML provides a compelling case for the extension of immunotherapeutic approaches which target dysregulated cell surface antigens expressed on the surface of LSC rather than abnormalities in intracellular signaling pathways. The GVL effect in which the donor immune system targets “foreign” antigens expressed on the leukemic blast is the most widely exploited form of immunotherapy in clinical practice, but there is growing interest in the clinical benefit of strategies by which the patient’s own immune system can be manipulated to exert an anti-leukemic effect. A number of lines of evidence attest the presence of a potent GVL effect in patients allografted for AML. These include the demonstration that relapse risk is reduced in patients who develop GVHD and, a compelling observation by Bacigalupo that reduction in the level of post-transplant immunosuppression, achieved by reducing the cyclosporine dose to 1  mg/kg in the first 20 days post-transplant, markedly reduces the risk of disease relapse (Fig. 2-1) [18–20].

Fig.  2-1.  Impact of post-transplant cyclosporine (CyA) dose on disease relapse in patients allografted for AML in first CR [18]

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML 

The major factor limiting the effective exploitation of GVL effect in patients with high-risk AML is our continued inability to develop transplant protocols which effectively dissociate GVL from severe, potentially fatal, acute, and chronic GVHD. Putative targets of the GVL reaction include minor histocompatibility antigens such as HA-1, HA-2 and H-Y, and the leukemic-specific antigens WT1 and proteinase 3 [21–25]. However, attempts to target mHAgs such as HA-1 have been hampered by the rare frequency of this allele and its HLA restriction. In contrast, antigens such as WT1 represent an attractive option given its over-expression in up to 70% of patients with AML [26, 27]. It is clear, however, that further characterization of the immunogenicity of the AML stem cell will be vital if we are to improve the current immunotherapeutic strategies in high-risk AML [25]. The prospect of exploiting an autologous immune response for clinical benefit has been supported by the demonstration that gemtuzumab ozogamicin (GO), a monoclonal antibody to the putative LSC antigen CD33, can salvage patients with relapsed AML [28]. Based on this encouraging experience, humanized antibodies to a number of other antigens expressed on leukemic progenitors and LSC are currently under clinical trials in high-risk AML. Recent studies demonstrating the presence of an immune response to leukemiaspecific antigens such as WT1 and proteinase 3 has led to the development of strategies designed to induce an autologous T-cell response using either peptide vaccination or TCR gene transfer [29]. Early phase clinical trials studying the effect of peptide vaccination with immunodominant epitopes of WT1 or proteinase 3 confirm that it is possible to augment these responses in  vitro although compelling evidence of clinical benefit is awaited. In the future it will be important to define how such a strategy can be utilized to improve the outcome of allogeneic transplantation.

3.  Preparative Regimens in AML The clinical studies which, over the past three decades, have established a central role for allogeneic transplantation in AML therapy have been achieved using myeloablative conditioning regimens. It was initially unclear whether reduced intensity allografts would possess the capacity to deliver long-term disease-free survival in patients with AML. Whilst it is now evident that such regimens are also capable of delivering durable long-term remissions, a myeloablative conditioning regimen should continue to be viewed as the “gold standard” preparative regimen at least until the results of prospective studies of reduced intensity transplant regimens are available.

4.  Outcome in Patients with AML Transplanted Using a Myeloablative Conditioning Regimen 4.1.  Patients in First Complete Remission (CR1) Randomized controlled trials assessing the role of allogeneic transplantation in the management of patients in CR1 have been difficult to perform. Obstacles have not only included the randomization biases introduced because of the fixed perceptions of either physicians or patients, but also the very real problem

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that the allograft arm may include a smaller proportion of patients with highrisk disease, given the propensity of such patients to relapse before they reach transplant. The only effective approach which allows these biases to be removed is the use of a “donor versus no-donor” analysis which exploits the availability of an HLA identical sibling donor as a form of biological randomization. Although weakened by the fact that not all patients with an available donor will be transplanted, “donor versus no-donor” analyses have proved the only unbiased statistical methodology by which the benefit of a sibling allograft can be assessed [30]. A number of international co-operative groups have reported the results of “donor versus no-donor” analyses in the management of younger adults with AML in CR1 [31–35]. All but one study reported an improvement in the disease-free survival in patients with a donor (Tables 2.1 and 2.2). Although no individual study showed a statistically significant survival benefit – probably because a proportion of patients in the “no-donor” arm could be effectively salvaged by a transplant in CR2 – a recent meta-analysis has demonstrated both an improved disease-free and overall survival in the donor group [32]. Importantly, these studies demonstrate that presentation karyotype and patient age are powerful tools in identifying who will benefit from a sibling allograft. Allogeneic transplantation delivers a clear survival advantage in patients with intermediate or adverse risk cytogenetics [32]. Indeed the risk of relapse is so high in patients with adverse risk cytogenetics that allogeneic transplantation using an unrelated donor is indicated in all CR1 patients with an available donor [36]. In contrast, allogeneic transplantation should not be performed in CR1 patients with good risk cytogenetics whose outcome with chemotherapy can be predicted to be relatively good. This approach is also supported by the 90% salvage rate achievable in patients with good Table  2-1.  A donor-vs.-no-donor analysis of impact of sibling allogeneic transplantation on overall survival (OS) and disease-free survival (DFS) in patients with AML in CR1. OS(%)

DFS(%)

Study

Donor no-donor

p

Donor

no-donor

GOELAM [31]

53

53

NS

44

38

0.6

HOVON [32]

54

46

NS

48

37

<0.001

BGMT [33]

65

51

NS

66

42

<0.05

MRC [34]

56

50

NS

50

42

0.001

EORTC [35]

48

40

NS

46

33

0.01

Table  2-2.  Relapse rates and toxicity in “donor” and “no-donor” arms. Relapse rate

Toxic death

Donor

no-donor

Donor

no-donor

GOELAM [31]

37

54

22

 3

EORTC [35]

42

63

21

12

MRC [34]

36

52

19

 8

p

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML 

risk cytogenetics who relapse in contrast to salvage rates of 40% or less in patients with intermediate or adverse risk cytogenetics [37]. Age is also an important determinant of outcome since the TRM of a myeloablative allograft rises sharply above the age of 35–40 years [37]. In addition to defining patients who clearly benefit from allogeneic transplantation, these studies have also identified those in whom a myeloablative allograft in CR1 is not indicated. These include older patients (>40–45 years) and those with favorable cytogenetics in whom any reduction in relapse risk is offset by the toxicity of transplantation. Much work remains to be done in order to identify the patients with intermediate risk cytogenetics requiring an allograft. According to Cornelissen et al., the risk of disease relapse must be greater than 35% ,before a survival benefit is likely to be conferred by a sibling allograft in a patient under the age of 40 years [32]. Recently, molecular markers which can predict the relapse risk of patients with intermediate risk cytogenetics, who are treated with chemotherapy alone, have been predicted. The demonstration that acquired mutations of a number of genes such as NPM1 and FLT3 can be used to predict survival, has allowed the identification of different subgroups including a population of patients (NPM1 +ve, FLT3 ITD –ve) who may not benefit from transplantation [38, 39]. Immunophenotypic quantitation of minimal residual disease, after induction or consolidation chemotherapy, also predicts relapse risk allowing effective risk stratification, and future prospective trials will be vital for validating this additional method of risk stratification [40]. 4.2.  Patients Beyond CR1 Salvage chemotherapy can induce a second complete remission (CR2) in upward of 40% of patients who relapse after an initial treatment with chemotherapy, but durable responses are rare [41]. Whilst a proportion of patients with good risk cytogenetics who relapse appear to be cured using only chemotherapy, this is rarely the case in patients with intermediate or adverse risk cytogenetics [42]. In contrast, registry data demonstrates long-term disease-free survival rates of 40–50% for patients who undergo a myeloablative sibling or unrelated donor transplant in CR2 [36, 43, 44]. In these patients, additional courses of chemotherapy prior to transplantation, once a second remission has been achieved seems to have no benefit: rather it is important to ensure that patients should instead proceed as swiftly as possible for transplantation [45]. The role of allogeneic transplantation in the management of patients with primary refractory disease remains controversial. A number of centers report long-term disease-free survival rates in the range of 25–45% in patients with AML resistance to two or more lines of induction chemotherapy who have been transplanted using a sibling or unrelated donor [46–49]. The patients most likely to benefit include those with intermediate risk cytogenetics who are allografted using an HLA identical sibling donor. Prompt transplantation is critical if such an approach is to be effective, and therefore, tissue typing of siblings and an unrelated donor search is indicated in younger (<45 years) patients failing to enter remission with their first course of chemotherapy.

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5.  Unresolved Issues in Myeloablative Allogeneic Transplantation in AML The main causes of treatment failure in patients allografted for AML are transplant-related toxicity (principally, acute and chronic GVHD) and disease relapse. Both are susceptible to manipulation by judicious adjustment of the three most important components of the transplant protocol: the type of preparative regimen used, whether T-cell depletion is employed, and the choice of stem cell source. 5.1.  What is the Optimal Conditioning Regimen? The most widely used myeloablative conditioning regimens in AML combine either cyclophosphamide and TBI (Cy/TBI) or busulphan (Bu) and cyclophosphamide (Bu/Cy). A series of randomized studies in the 1990s compared these regimens in patients with myeloid malignancies undergoing a sibling allograft [50–53]. Although there was a broad equivalence of outcome in patients with early phase CML and AML in CR1, there was a survival advantage associated with the use of Cy/TBI in patients with advanced phase AML [54–56]. It is now clear that the pharmacokinetics of oral Bu are highly unpredictable. This variability significantly impacts the outcome of transplantation in myeloid malignancies as low Bu levels have been shown to be associated with an increased risk of relapse whilst high Bu levels are associated with excessive transplant toxicity – principally, veno-occlusive disease [57, 58]. It is, therefore, surprising that despite the unpredictable bioavailability of oral Bu, previous randomized studies have demonstrated broad equivalence in the outcome between patients transplanted using Cy/TBI or Bu/Cy regimens. This raised the possibility that Bu-based regimens might be superior to Cy/ TBI if methods could be developed allowing for more effective delivery of this very active anti-leukemic agent. In the past decade, two approaches which allow consistent Bu levels to be achieved were proposed. In the first, real-time pharmacokinetic calculations are used to make adjustments to the doses of oral Bu prescribed. This approach allows a well-tolerated Bu level to be achieved (targeted TBu/Cy) in the great majority of patients. Alternatively, a recently developed intravenous preparation of Bu can be used (iv Bu/Cy) to deliver consistent drug levels [59, 60]. Using a TBu/Cy regimen, the Seattle group reported markedly reduced transplant toxicity and relapse rates in patients allografted for CML and secondary AML [61]. Similar encouraging results have been reported in preliminary studies using an iv Bu/Cy regimen [62]. A randomized comparison of either or both of these regimens with Cy/TBI in patients transplanted for myeloid disease is therefore required. 5.2.  What is the Role of T-Cell Depletion Strategies in Myeloablative Allografts There is no consensus over the role of T-cell depletion in the design of myeloablative preparative regimens in AML. Enthusiasts of T-replete allografts cite the potency of the GVL effect in AML and the limited salvage options in patients who relapse post-transplant as justification for the use of unmanipulated stem cells. These arguments are countered by a school of thought which

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML 

highlights acute and chronic GVHD as the major causes of transplant toxicity and argues that the low rate of acute GVHD in T-depleted allografts permits intensification of the preparative regimen [63]. In the absence of any randomized studies, many units utilize T-replete strategies in sibling allografts and some form of T-cell depletion (using either anti-thymocyte globulin (ATG) or alemtuzumab) in unrelated donor transplants [36]. 5.3.  What is the Optimal Stem Cell Source? The use of peripheral blood stem cells (PBSC) compared with bone marrow (BM) harvested progenitors results in faster neutrophil and platelet engraftment, and appears to be associated with a lower TRM in patients undergoing a sibling allograft for advanced phase disease [64]. Accumulating evidence suggests that these benefits may be offset by an increased risk of chronic GVHD in patients with early phase disease who are transplanted using PBSC, and in children there is evidence that the use of mobilized progenitors prejudices outcome [65]. In unrelated donor transplants, the optimal stem cell source is unknown. The impact of the stem cell dose on the risk of disease relapse is of significance, and a number of papers identify a reduced relapse risk in patients receiving a stem cell inoculum over 4 × 106 CD34+ cells/kg. It has been postulated that this may be consequent to an increased GVL effect [66, 67]. Reports that the risk of chronic GVHD may be increased in recipients of >8 × 106 CD34+ cells/kg suggest, however, that there may be an upper limit to the optimal stem cell dose in the setting of T-replete allografts [68]. Improved tissue typing has made a major contribution to the development in the outcome of patients with AML undergoing an unrelated donor transplant. Disease-free survival rates in the range of 40–60% are achievable using a myeloablative conditioning regimen in CR1 patients [36, 44, 69]. A potentially important advance is the recent demonstration that the excellent results achievable in children using cord blood, are replicable in adults, provided the dose of nucleated cells transplanted is adequate [70]. It appears that this can reliably be achieved in many patients by the transplantation of two, rather than one, cord blood units [71]. Whilst GVHD and delayed immune reconstitution remain significant causes of mortality after cord blood transplantation, it now appears possible that this evolving transplant technology may have an important role to play in the treatment of patients with high-risk AML.

6.  The Emerging Role of Reduced Intensity Transplants in the Management of AML The notion, advanced in the late 1990s, that it might be possible to extend a potentially curative GVL effect to older patients by employing less toxic immunosuppressive preparative regimens has been triumphantly vindicated in the past decade. A number of different RIC regimens have been evaluated over this period. The two most commonly used classes of reduced intensity regimens incorporate either a non-myeloablative dose (200  cGy) of TBI or immunosuppressive doses of fludarabine in conjunction with conventional chemotherapy. Both classes of regimen clearly reduce the transplant toxicity substantially, allowing patients up to the age of 70 years to be viewed as potential allograft candidates [4, 5, 72]. It is only recently, however, that it has

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been possible to demonstrate that such regimens deliver durable long-term remissions in AML and prospective studies aimed at defining the precise role of RIC allografts in the management of both older and younger patients with AML are, therefore, now required. 6.1.  Outcome of Reduced Intensity Allografts in AML A number of reduced intensity conditioning regimens have been evaluated in adult AML. The most fundamental difference in approach involves whether T-cell depletion is employed as a central component of the preparative regimen or not. T-replete strategies have been shown to deliver DFS rates in excess of 50% in patients with high-risk AML in CR1 or CR2 with broadly similar results being reported using either a low dose TBI or fludarabine/melphalan regimen [73, 74]. The major limitation of a T-replete approach is the high risk of severe GVHD which not only represents a major cause of morbidity and mortality but also limits the potential for manipulating a GVL effect posttransplant. These concerns have resulted in the incorporation T-cell depleting antibodies, principally alemtuzumab and ATG into fludarabine-based reduced intensity protocols. A number of recent Phase II studies have demonstrated that such an approach significantly reduces the risk of both acute and chronic GVHD, without apparently compromising the ability of these regimens to deliver a potent, and durable, anti-leukemic activity in patients whose outlook with conventional chemotherapy would be extremely poor. Thus, both the French co-operative group, who use fludarabine, Bu and ATG [75, 76], and the UK collaborative group who use fludarabine, melphalan and alemtuzumab have demonstrated 3 year disease-free survival rates in excess of 50% in patients transplanted in CR1 or CR2 [74, 77, 78] (Fig. 2-2). In order to exclude potential biases favoring transplant, these results will require further confirmation in prospective trials using a “donor vs. no-donor” analysis. It is, however, noteworthy that the first of such studies has demonstrated a clear increase in both disease-free survival and overall survival in patients with a donor [79]. Further work is also required to identify more precisely, patients who will benefit from allogeneic transplantation. Importantly, both the T-replete and T-deplete strategies have shown that acquisition of morphological remission prior to transplant is critical if patients are to survive long term. It is also of interest that a procedure whose anti-leukemic potential is predicated on a T-cell mediated graft-versus-leukemic activity appears to remain effective despite T-cell depletion. This observation, confirmed by a number of groups, demonstrates the importance of further research into identifying both the target and the cellular effectors of the GVL reaction in AML.

7.  Strategies to Improve the Outcome of Reduced Intensity Allogeneic Transplantation in AML The major cause of treatment failure in patients transplanted using a RIC regimen is disease relapse. In patients transplanted in remission, the risk of relapse is in the range of 30–40%. Disease relapse occurs predominantly in the first year post-transplant -- in patients transplanted using an alemtuzumab containing regimen, 85% of those patients destined to relapse do so within the first year post-transplant [77] (Fig. 2-3). Therefore, approaches which reduce the

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML 

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Fig. 2-2.  Outcome of patients undergoing reduced intensity allogeneic transplantation for AML. Patients were transplanted using a fludarabine/melphalan/alemtuzumab containing reduced intensity regimen. Disease status during transplant is the most important predictor of outcome [77].

Fig. 2-3.  Kinetics of disease relapse after reduced intensity allogeneic transplantation using a fludarabine/melphalan/alemtuzumab regimen [77].

relapse risk must focus on either optimizing cytoreduction prior to transplant, increasing the anti-leukemic activity of the conditioning regimen or maximising the GVL effect in the first few weeks or months post-transplant.

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The observation that disease stage is an important predictor of disease relapse raises the possibility that minimal residual disease status immediately prior to transplant will be an important predictor of relapse risk. Whilst this hypothesis has not been formally tested, there is interest in the use of either further courses of chemotherapy as a way to reduce the risk of disease relapse. In this context it is of interest that the impressive results reported by the French Collaborative Group are achieved using a T-depleted regimen which incorporates a prior autograft. The use of intravenous preparations of Bu [80] or targeted radioimmunotherapy represent other possible approaches by which the anti-leukemic activity of the preparative regimen can be increased without a concomitant rise in transplant toxicity. The other strategy by which the risk of relapse might be reduced is the augmentation of the GVL effect post-transplant, particularly in recipients of T-cell depleted grafts. There is, therefore, interest in examining the impact on relapse risk of manipulating either the degree of T-cell depletion (by reducing the dose of ATG or alemtuzumab) or the intensity of post-transplant immunosuppression. Alternative approaches to augment a GVL response include the use of prophylactic donor lymphocyte infusions (DLI) in patients with mixed T-cell chimerism [81]. Such an approach is constrained by the risk of severe, potentially life-threatening, GVHD associated with DLI administration in the first 12 months post-transplant. This limits both the lymphocyte dose which can be safely administered and, in unrelated transplant recipients, represents a significant and largely unpredictable risk of morbidity and mortality in the first year post-transplant [82–84]. At present, there is no consensus concerning the role of DLI after RIC transplants and prospective studies examining dose, timing, and source of DLI (GCSF stimulated or not) are required [85]. Whether the use of peptide vaccination to candidate immunodominant epitopes implicated in a GVL reaction will reduce the relapse risk without the complication of GVHD remains to be seen. An alternative approach which needs to be explored involves the use of adjunctive leukemic-specific therapy post-transplant, such as a FLT3 inhibitor or a demethylating agent, in the hope that the kinetics of disease relapse can be manipulated so that the timing of DLI can be postponed to a time at which it can be administered with less toxicity. Two major barriers exist, preventing the wider use of reduced intensity allografts in AML: the lack of a suitable sibling or unrelated donor in a proportion of patients and the presence of refractory or resistant leukemia in many. The encouraging results reported by a number of groups using mismatched umbilical cord blood units are, therefore, extremely important as a method of increasing the donor availability and promising results have been reported in adults with high-risk AML who lack an unrelated donor [71, 86, 87]. The ground-breaking work of Kolb’s group who has shown that incorporation of a course of intensive chemotherapy several days before commencing the conditioning regimen followed by an aggressive post-transplant immunotherapy improves the outcome of patients with active disease, and offers the prospect of successfully transplanting even patients with resistant leukemia [88, 89].

8.  Conclusions Significant progress has been made in the last decade in defining and extending the role of allogeneic transplantation in the management of patients with

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML 

AML. As a result we can now identify, with some degree of precision, a sizeable population of patients whose outcome with chemotherapy is poor and who benefit from allogeneic transplantation. Equally importantly, patients who should not be exposed to the potential harm of an allograft can also now be identified. The ability of reduced intensity preparative regimens to decrease the transplant toxicity has allowed the extension of allogeneic transplantation to older adults with AML. However, disease relapse remains a significant cause of treatment failure in patients transplanted using a reduced intensity regimen. The major challenges for the next decade will, therefore, be the further refinement of our ability to identify patients whose prospect of long-term disease-free survival without transplantation is poor and the development of strategies which improve transplant outcome by reducing the relapse rate without increasing the risk of GVHD.

References 1. Gratwohl A, Baldomero H, Frauendorfer K, Urbano-Ispizua A (2006) EBMT activity survey 2004 and changes in disease indication over the past 15 years. Bone Marrow Transplant 37(12):1069–1085 2. Frohling S, Schlenk RF, Kayser S, Morhardt M, Benner A, Dohner K et al (2006) Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: Results from AMLSG trial AML HD98-B. Blood 108(10):3280–3288 3. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ et al (2001) The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): Analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98(5):1312–1320 4. Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P et  al (1997) Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative therapy. Blood 89(12):4531–4536 5. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al (2001) Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97(11):3390–3400 6. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737 7. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et  al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344(14):1031–1037 8. Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R et al (2006) A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108(10):3262–3270 9. Harousseau JL, Lancet JE, Reiffers J, Lowenberg B, Thomas X, Huguet F et  al (2007) A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood 109(12):5151–5156 10. Lancet JE, Gojo I, Gotlib J, Feldman EJ, Greer J, Liesveld JL et al (2007) A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 109(4):1387–1394 11. Bullinger L, Valk PJ (2005) Gene expression profiling in acute myeloid leukemia. J Clin Oncol 23(26):6296–6305 12. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM et al (2004) Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350(16) 1617–1628

21

22 

C. Craddock 13. Higuchi M, O’Brien D, Kumaravelu P, Lenny N, Yeoh EJ, Downing JR (2002) Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1(1):63–74 14. Frohling S, Scholl C, Gilliland DG, Levine RL (2005) Genetics of myeloid malignancies: Pathogenetic and clinical implications. J Clin Oncol 23(26):6285–6295 15. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C (2006) Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol 7(10):1048–1056 16. Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA et al (2001) Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98(8):2301–2307 17. Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ et al (2002) Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci USA 99(25):16220–16225 18. Bacigalupo A, Vitale V, Corvo R, Barra S, Lamparelli T, Gualandi F et al (2000) The combined effect of total body irradiation (TBI) and cyclosporin A (CyA) on the risk of relapse in patients with acute myeloid leukaemia undergoing allogeneic bone marrow transplantation. Br J Haematol 108(1):99–104 19. Bacigalupo A, Van Lint MT, Occhini D, Gualandi F, Lamparelli T, Sogno G et al (1991) Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood 77(7):1423–1428 20. Locatelli F, Zecca M, Rondelli R, Bonetti F, Dini G, Prete A et  al (2000) Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: Results of a randomized trial. Blood 95(5):1572–1579 21. Greiner J, Dohner H, Schmitt M (2006) Cancer vaccines for patients with acute myeloid leukemia – definition of leukemia-associated antigens and current clinical protocols targeting these antigens. Haematologica 91(12):1653–1661 22. Rezvani K, Yong AS, Savani BN, Mielke S, Keyvanfar K, Gostick E et al (2007) Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes following allogeneic stem cell transplantation for acute lymphoblastic leukemia (ALL). Blood 110(6):1924–1932 23. Scheibenbogen C, Letsch A, Thiel E, Schmittel A, Mailaender V, Baerwolf S et al (2002) CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 100(6):2132–2137 24. Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA et al (2003) Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 100(5):2742–2747 25. Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A et  al (2006) Expression of tumor-associated antigens in acute myeloid leukemia: Implications for specific immunotherapeutic approaches. Blood 108(13):4109–4117 26. Lapillonne H, Renneville A, Auvrignon A, Flamant C, Blaise A, Perot C et  al (2006) High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 24(10):1507–1515 27. Oka Y, Tsuboi A, Taguchi T, Osaki T, Kyo T, Nakajima H et al (2004) Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci USA 101(38):13885–13890 28. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H et al (2001) Efficacy and safety of gemtuzumab ozogamicin in patients with CD33positive acute myeloid leukemia in first relapse. J Clin Oncol 19(13):3244–3254 29. Xue SA, Gao L, Hart D, Gillmore R, Qasim W, Thrasher A et al (2005) Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene-transduced human T cells. Blood 106(9):3062–3067

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML  30. Wheatley K (2002) Current controversies: Which patients with acute myeloid leukaemia should receive a bone marrow transplantation? – a statistician’s view. Br J Haematol 118(2):351–356 31. Harousseau JL, Cahn JY, Pignon B, Witz F, Milpied N, Delain M et  al (1997) Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood 90(8):2978–2986 32. Cornelissen JJ, van Putten WL, Verdonck LF, Theobald M, Jacky E, Daenen SM et al (2007) Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: Benefits for whom? Blood 109(9):3658–3666 33. Jourdan E, Boiron JM, Dastugue N, Vey N, Marit G, Rigal-Huguet F et al (2005) Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: An intent-to-treat long-term analysis of the BGMT experience. J Clin Oncol 23(30):7676–7684 34. Burnett AK, Wheatley K, Goldstone AH, Stevens RF, Hann IM, Rees JH et  al (2002) The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: Results of the UK MRC AML 10 trial. Br J Haematol 118(2):385–400 35. Suciu S, Mandelli F, de Witte T, Zittoun R, Gallo E, Labar B et al (2003) Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): An intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood 102(4):1232–1240 36. Das-Gupta EP, Russell NH, Shaw BE, Pearce RM, Byrne JL (2007) Long-term outcome of unrelated donor transplantation for AML using myeloablative conditioning incorporating pretransplant Alemtuzumab. Biol Blood Marrow Transplant 13(6):724–733 37. Burnett AK (2002) Current controversies: Which patients with acute myeloid leukaemia should receive a bone marrow transplantation? – an adult treater’s view. Br J Haematol 118(2):357–364 38. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et  al (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood 106(12):3740–3746 39. Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK et  al (2007) The impact of FLT3 internal tandem duplication mutant level, number, size and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111(5):2776–2784 40. San Miguel JF, Martinez A, Macedo A, Vidriales MB, Lopez-Berges C, Gonzalez M et al (1997) Immunophenotyping investigation of minimal residual disease is a useful approach for predicting relapse in acute myeloid leukemia patients. Blood 90(6):2465–2470 41. Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF et al (2005) Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 23(9):1969–1978 42. Thalhammer F, Geissler K, Jager U, Kyrle PA, Pabinger I, Mitterbauer M et  al (1996) Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: A retrospective single-center study. Ann Hematol 72(4):216–222 43. Gale RP, Horowitz MM, Rees JK, Gray RG, Oken MM, Estey EH et  al (1996) Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia 10(1):13–19

23

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C. Craddock 44. Tallman MS, Dewald GW, Gandham S, Logan BR, Keating A, Lazarus HM et al (2007) Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Blood 110(1):409–417 45. Tallman MS, Rowlings PA, Milone G, Zhang MJ, Perez WS, Weisdorf D et  al (2000) Effect of postremission chemotherapy before human leukocyte antigenidentical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 96(4):1254–1258 46. Fung HC, Stein A, Slovak M, O’Donnell MR, Snyder DS, Cohen S et al (2003) A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: Impact of cytogenetic characteristics on transplantation outcome. Biol Blood Marrow Transplant 9(12): 766–771 47. Oyekunle AA, Kroger N, Zabelina T, Ayuk F, Schieder H, Renges H et al (2006) Allogeneic stem-cell transplantation in patients with refractory acute leukemia: A long-term follow-up. Bone Marrow Transplant 37(1):45–50 48. Wong R, Shahjahan M, Wang X, Thall PF, De Lima M, Khouri I et  al (2005) Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant 11(2):108–114 49. Biggs JC, Horowitz MM, Gale RP, Ash RC, Atkinson K, Helbig W et al (1992) Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 80(4):1090–1093 50. Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie A, Jouet JP et  al (1992) Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: A randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: A report from the Group d’Etudes de la Greffe de Moelle Osseuse. Blood 79(10):2578–2582 51. Clift RA, Buckner CD, Thomas ED, Bensinger WI, Bowden R, Bryant E et  al (1994) Marrow transplantation for chronic myeloid leukemia: A randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 84(6):2036–2043 52. Devergie A, Blaise D, Attal M, Tigaud JD, Jouet JP, Vernant JP et  al (1995) Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: A randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: A report from the French Society of Bone Marrow. Blood 85(8):2263–2268 53. Ringden O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L et  al (1994) A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: A report from the Nordic Bone Marrow Transplantation Group. Blood 83(9):2723–2730 54. Socie G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ et  al (2001) Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: Long-term follow-up of 4 randomized studies. Blood 98(13):3569–3574 55. Ringden O, Remberger M, Ruutu T, Nikoskelainen J, Volin L, Vindelov L et  al (1999) Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: Long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. Blood 93(7):2196–2201 56. Litzow MR, Perez WS, Klein JP, Bolwell BJ, Camitta B, Copelan EA et al (2002) Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission. Br J Haematol 119(4):1115–1124

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML  57. Ljungman P, Hassan M, Bekassy AN, Ringden O, Oberg G (1997) High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients. Bone Marrow Transplant 20(11):909–913 58. Slattery JT, Clift RA, Buckner CD, Radich J, Storer B, Bensinger WI et al (1997) Marrow transplantation for chronic myeloid leukemia: The influence of plasma busulfan levels on the outcome of transplantation. Blood 89(8):3055–3060 59. Deeg HJ, Storer B, Slattery JT, Anasetti C, Doney KC, Hansen JA et  al (2002) Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 100(4):1201–1207 60. Madden T, de Lima M, Thapar N, Nguyen J, Roberson S, Couriel D et al (2007) Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: A comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant 13(1):56–64 61. Chang C, Storer BE, Scott BL, Bryant EM, Shulman HM, Flowers ME et al (2007) Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: Similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood 110(4):1379–1387 62. Kim SE, Lee JH, Choi SJ, Ryu SG, Lee KH (2005) Morbidity and non-relapse mortality after allogeneic bone marrow transplantation in adult leukemia patients conditioned with busulfan plus cyclophosphamide: A retrospective comparison of oral versus intravenous busulfan. Haematologica 90(2):285–286 63. Papadopoulos EB, Carabasi MH, Castro-Malaspina H, Childs BH, Mackinnon S, Boulad F et  al (1998) T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: Freedom from relapse in the absence of graft-versus-host disease. Blood 91(3):1083–1090 64. Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R et  al (2001) Transplantation of bone marrow as compared with peripheral-blood cells from HLAidentical relatives in patients with hematologic cancers. N Engl J Med 344(3):175–181 65. Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza FR Jr, Ringden O et al (2004) Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 22(24):4872–4880 66. Bahceci E, Read EJ, Leitman S, Childs R, Dunbar C, Young NS et  al (2000) CD34+ cell dose predicts relapse and survival after T-cell-depleted HLA-identical haematopoietic stem cell transplantation (HSCT) for haematological malignancies. Br J Haematol 108(2):408–414 67. Nakamura R, Bahceci E, Read EJ, Leitman SF, Carter CS, Childs R et  al (2001) Transplant dose of CD34(+) and CD3(+) cells predicts outcome in patients with haematological malignancies undergoing T cell-depleted peripheral blood stem cell transplants with delayed donor lymphocyte add-back. Br J Haematol 115(1):95–104 68. Przepiorka D, Anderlini P, Saliba R, Cleary K, Mehra R, Khouri I et  al (2001) Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 98(6):1695–1700 69. Sierra J, Storer B, Hansen JA, Martin PJ, Petersdorf EW, Woolfrey A et al (2000) Unrelated donor marrow transplantation for acute myeloid leukemia: An update of the Seattle experience. Bone Marrow Transplant 26(4):397–404 70. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A et  al (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351(22):2276–2285 71. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE (2003) Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood 102(5):1915–1919

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C. Craddock 72. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al (1998) Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91(3):756–763 73. de Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C et al (2004) Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: Dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplant. Blood 104(3):865–872 74. Hegenbart U, Niederwieser D, Sandmaier BM, Maris MB, Shizuru JA, Greinix H et al (2006) Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol 24(3):444–453 75. Blaise DP, Michel Boiron J, Faucher C, Mohty M, Bay JO, Bardoux VJ et  al (2005) Reduced intensity conditioning prior to allogeneic stem cell transplantation for patients with acute myeloblastic leukemia as a first-line treatment. Cancer 104(9):1931–1938 76. Mohty M, Bay JO, Faucher C, Choufi B, Bilger K, Tournilhac O et  al (2003) Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood 102(2):470–476 77. Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G et  al (2005) Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 23(36):9387–9393 78. van Besien K, Artz A, Smith S, Cao D, Rich S, Godley L et al (2005) Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23(24): 5728–5738 79. Mohty M, de Lavallade H, Ladaique P, Faucher C, Vey N, Coso D et  al (2005) The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: A donor vs no donor comparison. Leukemia 19(6):916–920 80. de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R et al (2004) Oncedaily intravenous busulfan and fludarabine: Clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 104(3):857–864 81. Mohty M, Avinens O, Faucher C, Viens P, Blaise D, Eliaou JF (2007) Predictive factors and impact of full donor T-cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation. Haematologica 92(7):1004–1006 82. Dominietto A, Pozzi S, Miglino M, Albarracin F, Piaggio G, Bertolotti F et  al (2007) Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia. Blood 109(11):5063–5064 83. Marks DI, Lush R, Cavenagh J, Milligan DW, Schey S, Parker A et al (2002) The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 100(9):3108–3114 84. Peggs KS, Thomson K, Hart DP, Geary J, Morris EC, Yong K et al (2004) Doseescalated donor lymphocyte infusions following reduced intensity transplantation: Toxicity, chimerism, and disease responses. Blood 103(4):1548–1556 85. Kolb HJ, Schmid C, Buhmann R, Tischer J, Ledderose G (2005) DLI: Where are we know? Hematology 10(Suppl 1):115–116 86. Tse WW, Zang SL, Bunting KD, Laughlin MJ (2008) Umbilical cord blood transplantation in adult myeloid leukemia. Bone Marrow Transplant 41(5):465–472

Chapter 2  Full Intensity and Reduced Intensity Allogeneic Transplantation in AML  87. Majhail NS, Brunstein CG, Tomblyn M, Thomas AJ, Miller JS, Arora M et  al (2008) Reduced-intensity allogeneic transplant in patients older than 55 years: Unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Biol Blood Marrow Transplant 14(3):282–289 88. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ (2005) Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23(24):5675– 5687 89. Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D et al (2006) Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 108(3):1092–1099

27

sdfsdf

Chapter 3 Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL) Bella Patel, Anthony H. Goldstone, and Adele K. Fielding

1.  Introduction Conventional treatment for adult acute lymphoblastic leukemia (ALL) consists of sequentially administered cycles of combination chemotherapy involving an induction, consolidation/intensification, and maintenance phase which is modeled on clinical protocols developed for the treatment of childhood ALL. With this approach, even though a majority of patients (80–92%) achieve complete remission, only one-third of patient or less are long-term survivors. The long-term survival has not changed for over a decade [1–7]. Thus, consolidation of remission is vital in achieving long-term survival in this disease. Intensive myeloablative therapy followed by allogeneic stem cell transplant is an alternative to conventional protracted consolidation/maintenance chemotherapy, offering the advantage of delivering a maximum dose intensive regime with the added benefit of a potential graft versus leukemia (GVL) effect. Thus, in an attempt to reduce the risk of relapse and improve the outcome of adult patients with ALL, numerous trials incorporating allo-HSCT into the treatment algorithm have been conducted. More recent studies have helped to define the subsets of adult patients who are likely to derive the most benefit from an intensive treatment strategy [8–10].

2.  Prognostic Factors in Adult ALL ALL is biologically heterogeneous. A number of features are associated with the failure of treatment (Table  3-1). Perhaps the best characterized and universally agreed adverse features are: patient age over 35 years, a high white blood count which for B lineage ALL is agreed as >30 × 109/l and for T lineage >100,000 × 109/l, and the presence of the Philadelphia chromosome t(9;22) or BCR/ABL fusion gene. In recent years, other cytogenetic subgroups associated with poor outcomes have been identified and include leukemia which harbor the t(4;11) or MLL/AF4 fusion gene, complex karyotypes, and

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_3, © Springer Science + Business Media, LLC 2003, 2010

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Table 3-1.  Prognostic factors in adult ALL. Age WBC

>35 years

  B-lineage

>30 × 109/l

  T-lineage

>100,000 × 109/l

Immunophenotype

B-lineage ALL Cortical T-ALL

Cytogenetics

t(9;22)/BCR/ABL t(4;11)/MLL/AF4 Low hypodiploidy/near triploidy Complex karyotype (>5 abnormalities)

Treatment response

Late achievement of CR: >4 weeks Minimal Residual Disease late into therapy

low hypodiploidy/near triploidy [10, 11]. Immunophenotypic subgroups such as early T-ALL and pro-B ALL are also regarded by some groups as poor prognostic features [8, 11]. The speed and magnitude of treatment response has also been shown to predict treatment outcome. Some studies showing a late achievement of CR >4 weeks identifies a subset of patients with a high risk of relapse, although the recent UKALLXII/ECOG2993 study did not show a worse outcome for patients who took two cycles of induction therapy to achieve remission [9]. The involvement of the central nervous system during diagnosis probably has a worse prognosis, although long-term disease free survival can be achieved in this setting [12]. More recently, the demonstration of residual disease or occult leukemia cells detected by sensitive methods at various times in therapy has been shown to be of prognostic value, predicting a worse outcome [13, 14]. Importantly, this assessment appears to be independent of age and WBC. In adult ALL, demonstration of residual disease at later time points in therapy (~16 weeks) appears to be most predictive. A summary of prognostic factors is given in Table 3-1. Due to the poor prognostic outcome of patients in whom the Philadelphia chromosme is detected, physicians have for long followed an aggressive approach with the use of allo-HSCT in this group. Hence, the main body of this chapter will focus on the use of allo-HSCT in Ph negative ALL. A smaller section at the end will comment specifically on the use of allo-HSCT in Ph pos ALL.

3.  Sibling Allogeneic Hematopoietic Stem Cell Transplantation in First Remission (CR1) In adult patients lacking the Ph chromosome, the role of allo-HSCT to consolidate remission is controversial and has been the focus of intense study. It is generally accepted that randomization between allogeneic HSCT and no HSCT is neither feasible nor desirable, so trials which seek to determine the role of sibling allo-HSCT have generally employed a so-called “biological randomization.” Sibling allo-HSCT is assigned to those with an HLA compatible family donor and where a donor is not available, allocation to either chemotherapy or autologous hematopoietic stem cell transplantation

Chapter 3  Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL) 

31

Table 3-2.  Definitions of “high risk” for stratification in adult ALL trials. Trial

High risk features

LALA 87 Pethema

Ph +/Common ALL with age >35/WBC > 30 × 109/l, CR >4/52, Null ALL Age 30–50,WBC ³ 25 × 109/l, t(4;11)/11q23 rearrangement, t(1,19)

GMALL

WBC > 30,000 × 109/l, CR > 4/52, immunophenotype

JALSG 93

Any patient with Ph+, age >30 or WBC over 30,000 × 109/l

LALA 94

Any patient with CNS disease at diagnosis, CR beyond first induction; B lineage ALL with 11q23 rearrangements, t(1;19), WBC > 30,000 × 109/l,or myeloid markers

GOELAL02

Ph+, t(4;11), t(1,19) WBC > 30 × 109/l. CR after first induction, age >35

UKALL XII/ECOG 2993 Ph+

(auto-HSCT) or a randomization between the latter two treatments is carried out. The results for such studies are compared in a “donor versus no-donor” intention-to-treat basis. A summary of the available trials, comparing the results of allo-SCT in first CR in patients lacking the Philadelphia chromosome are given in Table 3-2. Generally, results indicate that allo-HSCT provides the most potent antileukemic therapy, significantly reducing the risk of relapse to a greater magnitude than either conventional chemotherapy or autoSCT. However, an overall survival benefit is not always demonstrated due to the high incidence of toxicity associated with the procedure. In the LALA 87 study, patients under the age of 40 years with a donor received an HLA-identical sibling HSCT, those over 50 years were treated with chemotherapy, and the remaining patients were randomized between chemotherapy and auto-HSCT. At 10 years there was a significant survival benefit for allo-SCT in patients with high-risk features [15]. The BGMT study randomized patients in remission; those with an HLA matched sibling donor to allo-HSCT and the others to auto-HSCT. The 3 year disease free survival was significantly higher in allo-SCT recipients [16]. Recent prospective studies have focused on applying allo-HSCT to highrisk patients alone. Table 3-2 shows the features that the various studies have used to categorize “high-risk.” In the LALA 94 trial [17], high-risk patients (i.e., those falling outside the standard risk criteria or those with CNS disease at presentation) were assigned allo-HSCT if a HLA matched donor was available while others were randomized between auto-SCT and standard chemotherapy. Those receiving a sibling allo-HSCT had significantly better outcomes (5 year overall survival, 45 vs. 23%) [17]. In the Goelam-02 study [18], only high-risk patients under the age of 50 years were offered allo-SCT in first remission if a HLA-matched sibling donor was available, those lacking a donor were assigned to auto-HSCT. A clear survival advantage was observed in the allo-HSCT group at 6 years. Other studies have failed to demonstrate improved outcomes from allo-SCT in first remission. Two case-controlled studies performed by the IBMTR showed no overall advantage for transplant over chemotherapy even when stratifying for risk [19, 20] However, owing to the retrospective nature of these studies and inherent selection biases, it is difficult to arrive at any definitive conclusions from these studies. The largest donor vs. no-donor analysis comes from the UKALL12/ECOG2993 study, where almost 500 patients were included in

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the analysis. There was a clear and statistically significant survival advantage to having a matched sibling donor. Indeed, a number of patients with a donor did not receive allo-HSCT so the advantage may even have been underestimated. However, this study introduced a cautionary note in those patients who were older than 40 years;even though there was a considerable decrease in relapse risk among those who had a donor, there was no survival advantage, due to a very high treatment-related mortality, approaching 39% at 2 years. Thus, there is likely to be an upper age limit for patients who can benefit from myeloablative allo-HSCT, and this will continue to limit the applicability of the procedure. Overall, one can conclude that despite differences in the criteria applied for high-risk features between studies, there is a large body of data to support the use of allo-HSCT in first remission in adult ALL patients with high-risk features other than old age. However, the inclusion of patients with Ph + ALL in the overall results of many studies does not allow specific assessment of the value of allo-HSCT in patients with high-risk features outside this cytogenetic group. For patients with standard-risk disease, the role of allo-HSCT is less well studied. However, results from the largest study to compare post-remission therapies in adult ALL, the UKALL XII/ECOG 2993 study has helped to answer this question. Patients younger than 50 years (55 since 2004) in the first CR were assigned to allo-HSCT if a matched sibling donor was available. The other patients were randomized to auto-HSCT or standard chemotherapy. A survival advantage was observed for the allogeneic transplant group as a whole but this was largely due to the improved survival in standard risk patients; EFS was 59% with a donor, compared to 41% without a donor.

4.  Allo-HSCT Beyond CR1 Allogeneic stem cell transplantation has the best potential for long-term OS when applied in CR1 compared to CR2. However, in a proportion of patients with relapsed disease, long-term remission can be gained by receipt of an allogeneic stem cell transplant. Analysis based on IBMTR data showed that the probability of survival in patients achieving second remission is 30% at 5 years [21]. In the largest reported study of 609 patients, with recurring ALL, the overall estimated survival at 5 years was 7% [22]. Receipt of a hematopoietic stem cell transplantation from either a related or unrelated source in patients who had previously been treated with chemotherapy resulted in a better outcome compared to chemotherapy alone (23 vs. 4%). The same study showed the outcome after relapse was very poor and was not influenced by prior therapy. However, when treatment received post-relapse was evaluated in patients with an equal chance of receiving allo-HSCT (i.e., those alive at the median time to transplant and not having had allo-HSCT in CR1), a better outcome was observed in those receiving allo-HSCT than in those receiving chemotherapy alone [22]. Among the few published systematic studies examining factors responsible for achieving long-term remission following allogeneic stem cell transplantation for relapsed ALL, the receipt of a transplant

Chapter 3  Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL) 

at second remission compared to a sustained relapse, appears to be associated with better results [22, 23].

5.  Unrelated Donor Stem Cell Transplantation (UD-SCT) In Philadelphia chromosome positive disease UD-SCT in first remission is regarded as standard therapy in the absence of a matched sibling donor. The alternative for those lacking a sibling donor in this situation is an auto-HSCT. A retrospective comparison performed by the IBMTR of patients treated with either of these therapeutic modalities for ALL did not demonstrate a superior survival for UD-HSCT despite a demonstrated lower relapse risk due to an extremely high TRM which approached >40% [21]. With improvements in supportive care, HLA matching and GVHD prophylaxis, the TRM in UD-HSCT is improving. Three published studies have examined the role of UD-HSCT performed in the first remission in adult patients with ALL [24–26]. The results reported from these studies and from registry data are encouraging and do not show wide differences in outcomes from UD-HSCT (DFS ~40–50%) compared to sibling allogeneic transplantation. Sincethe analysis of these studies include Ph + cases, the role of UD-HSCT in first remission in patients outside this cytogenetic group have not been exclusively studied. As less than one-third of patients will have a HLA compatible sibling donor, UD-HSCT could pose a reasonable therapeutic option and is currently the subject of ongoing study.

6.  Other Stem Cell Sources Despite increasing size of donor pools, it is not possible to find an eight of eight allelic matched unrelated donor for all individuals. Using donors who are not fully matched or turning to alternative sources of stem cells are options which may be considered by transplant units. In children, a recent, and a very extensive retrospective study comparing the outcomes of HSCT using marrow or cord blood was carried out in patients receiving MUD or umbilical cord blood HSCT for leukemia [27]. Greater than 60% of those included had a diagnosis of ALL, mostly beyond CR1. TRM was statistically significantly higher after transplant of HLA-antigen mismatched umbilical cord blood compared to fully matched bone marrow stem cells (relative risk 2.31 for two antigen mismatch, 1.88 for one antigen mismatch), although relapse rates were lower after two-antigen HLA-mismatched umbilicalcord-blood transplants (RR 0.54, p = 0.0045). The authors conclude that the data support the use of HLA-matched and even one- or two-antigen HLAmismatched umbilical cord blood in children with acute leukemia who need transplantation. These data do not specifically address the issue of children with Ph + ALL in CR1, but the conclusion from this study may be relevant to this situation. The current pan-European trial in pediatric Ph + ALL allows the use of umbilical cord blood as a source of stem cells for HSCT and is recommended for all children with donors (Table 3-3).

33

Treatment compared

Chemo/auto-SCT

Auto-SCT

Chemo/auto-SCT

Chemo

Chemo

Chemo

Chemo

Chemo/auto-SCT

Group

LALAb 87 [15, 54, 55]

BGMTb [16]

PETHEMAb ALL 93 [56]

JALSG 1998 [20]

GMALL 1981 and 1984 [19]

Gupta et al. [57]

JALSGb 93 [5]

EORTCb ALL3 2004 [58]

68 vs. 116

34 vs. 108

48 vs. 39

234 vs. 484

214 vs. 76

84 vs. 98

43 vs. 77

116 vs. 141

N donor vs. no-donor

6 year RFS/OS 38 vs. 37%/41 vs. 39% p = not sig

6 year OS 40 vs. 46% p = 0.58

3 year RFS 40 vs. 39% p = 0.74

9 year RFS 34 vs. 32% p > 0.2 standard risk/high risk groups p³05

Age >30 years: 30 vs. 26% p = 0.70

Age < 30 years: 69 vs. 22%

Age <30 years: 53 vs. 30% p = 0.02

38 vs. 56% p = 0.001

Not reported

3 year RR 40 vs. 61% p = 0.07

9 year RR 30 vs. 66% p < 0.0001

Age >30 years: 70 vs. 32% p < 0.0001

5 year RR

62 vs. 51% p = 0.28

5 year RR

12 vs. 62%

34 vs. 60%

Relapse% donor vs. no-donor

5 year RFS

5 year RFS 37 vs. 46% p ³ 0.05

5 year OS 35 vs. 44% p = 0.35

3 year RFS 68 vs. 26% p < 0.001

High risk patients 10 year OS 44 vs. 11% p = 0.009

All patients 10 year OS 46 vs. 31% p = 0.04

Outcome donor vs. no-donor

Table 3-3.  Trials evaluating sibling allo HSCT in adult ALL in CR1.

23.5 vs. 6.9% p = 0.0004

Not reported

29 vs. 5% p = 0.004

9 year 53 vs. 5% p < 0.0001

Age >30 years: 57 vs. 13% p < 0.0001

Age <30 years: 32 vs. 3%

5 year

Not reported

12 vs. 2%

16 vs. 3%

TRM% donor vs. no-donor

34  B. Patel et al.

Auto-SCT

Chemo

GOELALM-02b [18]

UKALLb XII/ECOG 2993 (Rowe et al.)

384 vs. 418

41 vs. 115

100 vs. 159

b 

Outcome analysis may also include patients with Ph chromosome positive disease Prospective randomized studies

a 

Chemo/auto-SCT

LALAb 94 Trial [17]

High risk 36 vs. 63 p£0.05

High risk 41 vs. 35/38 vs. 31% (p > 0.5) Standard 64 vs. 51/59 vs. 47 p£0.05 standard risk

5 year RR

10 vs. 49%

5 year RR 36 vs. 62% p = 0.001

5 year OS/DFS

5 year OS 75 vs. 40% p = 0.0027

5 year RFS 45 vs. 23% p = 0.007

<35 years: 26 vs. 12%

>35 years: 45%

6 month 15.4 vs. 6.9%

5 year 18 vs. 7% p = 0.01

Chapter 3  Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL)  35

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In adults, due to the close relationship between cell dose and hematopoietic recovery/risk of TRM, a major limitation to the use of cord blood is the difficulty in obtaining sufficient numbers of hematopoietic precursor cells. An earlier report of umbilical cord blood HSCT in adults confirmed a higher TRM in adults compared with matched unrelated HSCT, although mismatched unrelated donor stem cells carried equivalent mortality to cord blood [28]. Technological advances and approaches to increasing cell dose by using, for example, dual-cord units may ultimately yield a technique which is safe enough for wider investigation of HSCT for ALL in adults. HSCT using haploidentical donors is also a clinical consideration in high-risk ALL when matched unrelated donors are not found. Just over 60 cases relating to adult ALL have been reported since 1993, 15 of these cases were Ph + , approximately half were beyond CR1. The data have been recently reviewed in detail [29]. Although the techniques have improved greatly, good results obtained by single centers have been almost impossible to replicate outside these very experienced settings due to the high TRM, stemming from both rejection and severe GVHD. Currently, it is not possible to recommend this approach for wider use.

7.  Preparative Regimes and T-Cell Depletion The most commonly used preparative regimes for allogeneic transplantation in ALL consist of cyclophosphamide or etoposide plus TBI. There have been few studies comparing different preparative regimes. A comparison of cyclophosphamide and TBI with etoposide and TBI as conditioning regimes for patients undergoing sibling allografting for ALL showed no differences in relapse, DFS, or survival [30]. However, for CR2 patients improved outcomes were observed with TBI and etoposide or cyclophosphamide with ³13 Gy [31]. Regarding the role of T-cell depletion, there are few data that directly address this issue in this disease. However, a general viewpoint would be that the lower TRM observed after T-cell depletion is likely compensated by a higher relapse rate. Marks et al. reported a relapse rate of 40% when using CD34 antibody selection or alemtuzumab for T-cell depletion [32]. Whether T-cell depletion can be “fine tuned,” for example an optimal dose of in vivo alemtuzumab, defined to balance the mortality caused by GVHD against the relapse risk remains to be seen.

8.  Reduced Intensity Conditioning Reduced intensity conditioning (RIC) for allografts is an interesting option, particularly in older patients or those with co-morbidities. It is clear that non-myeloablative or RIC regimens can deliver a powerful graft-versustumor effect in many diseases but the success of this approach likely relates to both disease burden and tempo of the underlying disease. A recent study of relapse risk in patients with various malignancies treated with RIC-HSCT attests the fact that the highest relapse risk is in those patients with advanced lymphoid and myeloid malignancies [33]. To date there are scant published

Chapter 3  Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL) 

data on the use of RIC-HSCT conditioning in ALL. A small study of 22 patients with ALL, 11 of whom had Ph + disease and most of whom were at very high risk, many having relapsed after previous myeloablative therapy, was reported [34]. Not surprisingly, the only leukemia-free survivors were among those individuals treated in CR. Martino et al. [35] reported another small retrospective series of 27 RIC-HSCT treated older patients (mean age 50), with high-risk ALL. Forty-one percent were Ph + and 85% were beyond CR1. In this high-risk group, 2 year TRM was 23% and 2 year OS was 31%. The low TRM and moderate OS suggest that there may have been some survival benefit to the procedure that outweighed the toxicity. For ALL in CR2, a series of 43 RIC-HSCT in both adults and children was recently published in Mexico [36]. The regimen was chosen above myeloablative HSCT, partly for economic reasons. Only two of the patients were Ph + . ALL patients became full donor chimeras, and the relapse rate was high, in the order of 70%. OS at 3 years was 31%. However, outcome after relapse is known to be poor [22, 37] and this study does not preclude benefit to the procedure in earlier stages of the disease. Data in abstract form were recently presented from the City of Hope transplant centre in which a fludarabine and melphalan RIC conditioning regimen was used in 21 patients with ALL in or beyond CR1 in whom the median age was 46, an age at which the toxicity of myeloablative conditioning would be expected to be considerable [38]. The 100 day non-relapse mortality was 10%. High rates of acute and chronic GVHD were observed, which may in part be responsible for the remarkably good DFS (1 year DFS 70.9%). However, since follow up is short, it is possible that the high rate of graft versus host disease may result in a higher late nonrelapse mortality. However, it remains a reasonable hypothesis that patients with ALL at high risk of relapsing as well as at very high risk of TRM, could benefit from RIC-SCT, especially if the disease is in “remission” at the time of HSCT. The definition of “remission” may be of crucial importance here. For example, it is clear in Ph + ALL that detection of MRD by BCR-ABL predicts relapse [39, 40]. However, it is not clear whether RIC-HSCT would be able to overcome the additional risk factor of having detectable MRD preHSCT. It will be interesting to observe if the depth of remission, i.e. being MRD negative as compared to being only in morphological CR or cytogenetic remission could alter the outcome. Whether donor lymphocyte infusions in combination with tyrosine kinase inhibitors in patients with Ph + ALL [41] might be of value to treat patients with residual MRD post-RIC HSCT is also not clear. A planned UK-USA collaborative trial will evaluate RIC HSCT in older patients with Philadelphia chromosome negative disease at highest risk of relapse in whom the predicted treatment-related mortality precludes myeloablative alloHSCT.

9.  Allo-HSCT in Philadelphia Chromosome Positive ALL Allogeneic stem cell transplantation in CR1 is the treatment of choice in Ph positive (Ph + ve) ALL where the overall outcomes with standard chemotherapy are uniformly dismal with less than 15% of patients surviving long-term. The use of allo-HSCT in this subset of patients has recently been comprehen-

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sively reviewed [42]. Although there are no randomized controlled trials comparing the results of allogeneic transplantation with standard chemotherapy, the reported OS for allo-HSCT in first or is 42–47% which is a superior to results obtained with intensive or auto-SCT [43–47]. Furthermore, the results of UD-SCT in this disease approach that observed in related allo-SCT. Taking into account the very low chance of cure with chemotherapy and auto-HSCT, UD-SCT in first remission in eligible patients lacking a related family donor is generally regarded as standard treatment. The introduction of the specific BCR/ABL tyrosine kinase inhibitor, Imatinib, has the potential to change the standard treatment for Ph + ALL. A number of studies have incorporated Imatinib into the treatment schedule for Ph + patients. Imatinib is commonly co-administered with induction drugs with a rationale of increasing the CR rate and therefore patients eligible for first CR allo-HSCT [48]. The most recently reported study of imatinib in induction from the French national group GRAAL, supports the notion that the addition of imatinib to induction can increase the number of patients reaching HSCT. Imatinib was added to induction (early poor responders) or to consolidation (good early responders), and maintained until HSCT. In 45 patients, CR rate was 96%. Each one of the 22 patients reaching CR who had a donor actually received allogeneic SCT in first CR. Follow up so far is short but is estimated at 65% overall survival at 18 months [49]. Imatinib may also play a role in post-HSCT maintenance. A study in which all patients with Ph + ALL, who became BCR/ABL positive after HSCT, were given imatinib show some long-term responses to those responding to imatinib in this setting [50].

10.  Improving Outcomes of Transplantation in Adult ALL The challenges in improving transplant outcomes in ALL focus on three factors: reducing toxicity,developing a rationalized approach for the application of therapies, and better treatment of post-transplant relapse. Novel drugs such as keratinocyte growth factor, an epithelial mitogen has been shown to significantly reduce both the incidence and duration of severe oral mucositis in patients receiving myeloablative chemoradiotherapy before autologous peripheral blood progenitor cell transplantation [51–53]. Better treatment and prevention of GVHD, and treatment of opportunistic viral infections may further help to abrograte the high TRM. A risk-adapted approach might further improve overall outcome; by reserving intensive treatments for those at high risk of relapse whilst avoiding this approach in those more likely to be cured by standard chemotherapy. Thus, a better assessment of risk is fundamental in improving the overall outcomes for adult patients with ALL. MRD assessment by molecular or immunological methods is an evolving risk stratification tool. Risk adapted therapy based on MRD assessment is currently the subject of numerous ongoing international studies. Furthermore, there are emerging data to suggest that detection of residual disease pre- and post-transplant predicts treatment failure. These observations could form a rationale for further cytoreduction prior to myeloablative therapy or in the post-transplant context guide the application of immunomodulatory strategies.

Chapter 3  Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL) 

References 1. Pui CH, Evans WE (2006) Treatment of acute lymphoblastic leukemia. N Engl J Med 354:166–178 2. Gokbuget N, Hoelzer D, Arnold R et al (2000) Treatment of adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hematol Oncol Clin North Am 14:1307–1325 ix 3. Linker C, Damon L, Ries C, Navarro W (2002) Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 20:2464–2471 4. Annino L, Vegna ML, Camera A et al (2002) Treatment of adult acute lymphoblastic leukemia (ALL): Long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood 99:863–871 5. Takeuchi J, Kyo T, Naito K et al (2002) Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia 16:1259–1266 6. Kantarjian H, Thomas D, O’Brien S et  al (2004) Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 101:2788–2801 7. Durrant IJ, Prentice HG, Richards SM (1997) Intensification of treatment for adults with acute lymphoblastic leukaemia: Results of UK Medical Research Council randomized trial UKALL XA. Medical Research Council Working Party on Leukaemia in Adults. Br J Haematol 99:84–92 8. Hoelzer D, Thiel E, Loffler H et al (1988) Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71:123–131 9. Rowe JM, Buck G, Burnett AK et al (2005) Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 106:3760–3767 10. Moorman AV, Harrison CJ, Buck GA et  al (2007) Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 tria. Blood 109:3189–3197 11. Secker-Walker LM, Craig JM, Hawkins JM, Hoffbrand AV (1991) Philadelphia positive acute lymphoblastic leukemia in adults: Age distribution, BCR breakpoint and prognostic significance. Leukemia 5:196–199 12. Lazarus HM, Richards SM, Chopra R et al (2006) Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG E2993. Blood 108:465–472 13. Mortuza FY, Papaioannou M, Moreira IM et al (2002) Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol 20:1094–1104 14. Bruggemann M, Raff T, Flohr T et  al (2006) Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 107:1116–1123 15. Sebban C, Lepage E, Vernant JP et al (1994) Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 12:2580–2587 16. Attal M, Blaise D, Marit G et al (1995) Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group. Blood 86:1619–1628

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B. Patel et al. 17. Thomas X, Boiron JM, Huguet F et  al (2004) Outcome of treatment in adults with acute lymphoblastic leukemia: Analysis of the LALA-94 trial. J Clin Oncol 22:4075–4086 18. Hunault M, Harousseau JL, Delain M et  al (2004) Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: A GOELAMS trial. Blood 104:3028–3037 19. Zhang MJ, Hoelzer D, Horowitz MM et al (1995) Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee. Ann Intern Med 123:428–431 20. Oh H, Gale RP, Zhang MJ et al (1998) Chemotherapy vs HLA-identical sibling bone marrow transplants for adults with acute lymphoblastic leukemia in first remission. Bone Marrow Transplant 22:253–257 21. Levine JE, Harris RE, Loberiza FR Jr et  al (2003) A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 101:2476–2482 22. Fielding AK, Richards SM, Chopra R et  al (2007) Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109:944–950 23. Tavernier E, Boiron JM, Huguet F et  al (2007) Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA94 trial. Leukemia 21:1907–1914 24. Dahlke J, Kroger N, Zabelina T et al (2006) Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation. Bone Marrow Transplant 37:155–163 25. Kiehl MG, Kraut L, Schwerdtfeger R et  al (2004) Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol 22:2816–2825 26. Cornelissen JJ, Carston M, Kollman C et  al (2001) Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood 97:1572–1577 27. Eapen M, Rubinstein P, Zhang MJ et  al (2007) Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: A comparison study. Lancet 369:1947–1954 28. Laughlin MJ, Eapen M, Rubinstein P et al (2004) Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 351:2265–2275 29. Marks DI, Aversa F, Lazarus HM (2006) Alternative donor transplants for adult acute lymphoblastic leukaemia: A comparison of the three major options. Bone Marrow Transplant 38:467–475 30. Gassas A, Sung L, Saunders EF, Doyle JJ (2006) Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens. Bone Marrow Transplant 38:739–743 31. Marks DI, Forman SJ, Blume KG et al (2006) A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant 12:438–453 32. Marks DI, Bird JM, Cornish JM et  al (1998) Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia-positive acute lymphoblastic leukemia. J Clin Oncol 16:931–936

Chapter 3  Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia (ALL)  33. Kahl C, Storer BE, Sandmaier BM et  al (2007) Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 110(7):2744–2748 34. Arnold R, Massenkeil G, Bornhauser M et al (2002) Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease. Leukemia 16:2423–2428 35. Martino R, Giralt S, Caballero MD et  al (2003) Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukemia: A feasibility study. Haematologica 88:555–560 36. Gutierrez-Aguirre CH, Gomez-Almaguer D, Cantu-Rodriguez OG et  al (2007) Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: Results of a multicenter study. Bone Marrow Transplant 40(6):535–539 37. Tavernier E, Boiron JM, Huguet F et  al (2007) Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA94 trial. Leukemia 21(9):1907–1914 38. Stein A, O’Donnell M, Snyder DS et  al (2007) Reduced-Intensity Stem Cell Tansplantation for high-risk acute lymphoblastic leukaemia. Biol Blood Marrow Transplant 13:134 39. Preudhomme C, Henic N, Cazin B et al (1997) Good correlation between RT-PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL). Leukemia 11:294–298 40. Radich J, Gehly G, Lee A et  al (1997) Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood 89:2602–2609 41. Shimoni A, Kroger N, Zander AR et  al (2003) Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias. Leukemia 17:290–297 42. Fielding AK, Goldstone AH (2007) Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia. Bone Marrow Transplant 41:447–453 43. Dombret H, Gabert J, Boiron JM et al (2002) Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia-results of the prospective multicenter LALA-94 trial. Blood 100:2357–2366 44. Forman SJ, O’Donnell MR, Nademanee AP et al (1987) Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 70:587–588 45. Chao NJ, Blume KG, Forman SJ, Snyder DS (1995) Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 85:3353–3354 46. Barrett AJ, Horowitz MM, Ash RC et  al (1992) Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 79:3067–3070 47. Snyder DS, Nademanee AP, O’Donnell MR et al (1999) Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia 13:2053–2058 48. Wassmann B, Pfeifer H, Scheuring U et al (2002) Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Leukemia 16:2358–2365 49. de Labarthe A, Rousselot P, Huguet-Rigal F et al (2007) Imatinib combined with induction or consolidation chemotherapy in patients with de  novo Philadelphia

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B. Patel et al. chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 109:1408–1413 50. Wassmann B, Pfeifer H, Stadler M et  al (2005) Early molecular response to posttransplantation imatinib determines outcome in MRD + Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood 106:458–463 51. Spielberger R, Stiff P, Bensinger W et al (2004) Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351:2590–2598 52. von Bultzingslowen I, Brennan MT, Spijkervet FK et al (2006) Growth factors and cytokines in the prevention and treatment of oral and gastrointestinal mucositis. Support Care Cancer 14:519–527 53. Worthington HV, Clarkson JE, Eden OB (2006) Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev:CD000978 54. Thiebaut A, Vernant JP, Degos L et al (2000) Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am 14:1353–1366 x 55. Fiere D, Lepage E, Sebban C et  al (1993) Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 11:1990–2001 56. Ribera JM, Ortega JJ, Oriol A et al (1998) Late intensification chemotherapy has not improved the results of intensive chemotherapy in adult acute lymphoblastic leukemia. Results of a prospective multicenter randomized trial (PETHEMA ALL89). Spanish Society of Hematology. Haematologica 83:222–230 57. Gupta V, Yi QL, Brandwein J et  al (2004) The role of allogeneic bone marrow transplantation in adult patients below the age of 55 years with acute lymphoblastic leukemia in first complete remission: A donor vs no donor comparison. Bone Marrow Transplant 33:397–404 58. Labar B, Suciu S, Zittoun R et al (2004) Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin’s lymphoma for patients £50 years old in first complete remission: results of the EORTC ALL-3 trial. Haematologica 89:809–817

Chapter 4 Hematopoietic Progenitor Cell Transplantation for Treatment of Chronic Lymphocytic Leukemia Leslie A. Andritsos, John C. Byrd, and Steven M. Devine

1.  Introduction: Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by a highly variable clinical course. It is the most common adult leukemia in Western countries, and although according to the SEER database the median age of diagnosis is 72, approximately 30% of newly diagnosed patients will be younger than age 65 [1]. Like other chronic lymphoproliferative disorders, CLL is not curable with chemotherapy alone. While standard chemo-immunotherapy with purine nucleoside analog-based therapies may result in excellent overall responses and complete remissions in a majority of patients [2–4], for patients with poor responses to initial therapy or those who exhibit early relapses (i.e., within 6–12 months of completing therapy), there are diminishing FDA-approved treatment options available for salvage therapy. Recent studies have suggested that the response rates of standard chemotherapies in patients who relapse following fludarabine-based regimens are on the order of 20% [5, 6]. The average survival for this group of patients is measured in months. Thus, despite encouraging advances in initial therapy for CLL, outcomes are frequently disappointing once this therapeutic option has failed.

2.  Risk Stratification in CLL Recent studies have demonstrated that patients with CLL can be subdivided into prognostic categories based on IgVH mutational status [7–9], ZAP-70 expression [10], CD38 expression [11], and metaphase and interphase cytogenetic analysis [12]. Perhaps the most powerful and widely available of these is cytogenetic analysis [13]. In 2000, Dohner et  al. described the clinical outcomes of patients with four commonly identified interphase cytogenetic abnormalities. This study clearly demonstrated the impact of adverse cytogenetic risk factors on time to first treatment and overall survival, with patients with 17p13.1 and 11q22.3 deletions having the worst outcomes [12]. One study evaluating genetic and molecular risk factors affecting patients randomized to From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_4, © Springer Science + Business Media, LLC 2003, 2010

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receive either fludarabine plus cyclophosphamide or fludarabine alone found that interphase cytogenetic features were the only risk factors that predicted progression-free survival [13]. Several later studies have demonstrated that del(11q22.3) when given hyperfractionated cyclophosphamide (days 1–3) with fludarabine may lose its prognostic factor in younger patients. These studies taken together, in addition to other recent studies evaluating the impact of cytogenetic analysis on patient outcomes, indicate that for select high risk patients with del(17p13.1), alternative strategies should be considered earlier in the disease course.

3.  Autologous Transplantation for Treatment of CLL High-dose chemotherapy with autologous stem cell support has been used extensively in the treatment of high-grade lymphomas, with a proportion of patients achieving long-term disease-free survival. The applicability of this approach to low-grade lymphomas has been less clear. The first study published in 1993 by Rabinowe et  al. was a pilot study assessing the feasibility of myeloablative conditioning with autologous stem cell support [14]. Twelve patients with chemosensitive disease underwent conditioning with cyclophosphamide and total body irradiation followed by reinfusion of purged autologous marrow products. Five of 12 patients achieved a complete clinical response without excess early toxicity. These promising results led to a number of studies evaluating the efficacy of autologous transplantation in CLL. Provan et al. looked specifically at the role of achievement of minimal residual disease (MRD) by polymerase chain reaction (PCR) in 21 patients who underwent myeloablative conditioning followed by purged marrow stem cell infusion. This study was the first to demonstrate that achievement of an MRD-negative state correlated with improved clinical outcomes, and was the basis for a number of studies evaluating disease status peri-transplant and the risk of relapse [15]. These results also confirmed the existence of a dose effect in CLL, with longer remissions seen in patients who received high-dose chemoradiotherapy with achievement of MRD, further stimulating interest in this approach. This pilot study was followed by a Phase II study of 137 patients with poor risk CLL which was reported by Gribben et  al. in 2005 [16]. This study found low 100 day mortality (4%), but no difference in overall survival between the autologous and allogeneic groups at 6.5 years. There was no significant difference in overall survival between the groups, and no demonstration of a plateau in progression-free survival in patients undergoing autologous transplantation. Importantly, 12% of patients who had undergone autologous transplantation developed myelodysplastic syndrome or AML by 8 years of follow-up. In our experience, this complication arising in the setting of CLL virtually always results in a fatal outcome. Balancing earlier benefit versus late toxicity is an important consideration in developing new strategies for a chronic disease such as CLL. No randomized studies have been performed comparing autologous transplantation to standard chemotherapy; however, Dreger et  al. performed a risk-matched analysis comparing 66 patients who underwent sequential high-dose therapy including autologous transplantation with 291 patients who received conventional chemotherapy [17]. The groups were matched for age,

Chapter 4  Hematopoietic Progenitor Cell Transplantation for Treatment of CLL 

lymphocyte count, Binet stage, and IgVH mutational status, with 44 patients matching all four variables. This study found a survival benefit in the autograft group, with a 4-year progression-free survival of 69% and a 4-year overall survival of 94%. No plateau in progression-free survival was demonstrated. A similar comparison was conducted by the European Bone Marrow Transplant Group (EBMT) database as part of the French CLL Cooperative Group study [18] which compared 621 patients who underwent autografting to 630 patients who received conventional therapy, which has been published in abstract form. This study found a benefit in patients who were autografted within 18 months of diagnosis but no benefit when patients were autografted more than 18 months after diagnosis. It is clear from the studies that have been performed to date that the greatest benefit from autografting is seen in patients who have chemosensitive disease at the time of transplant, are in remission with a low tumor burden, and are able to achieve MRD-negative status following transplant. In this setting, multiple studies have demonstrated prolonged progression-free survival, with retrospective studies showing improved overall survival over comparator groups who received standard chemotherapy. However, such assessment comes with significant bias. Despite conditioning regimens containing high-dose chemotherapy and total body irradiation, the reported early mortality has been in the range of 2–10%, which is comparable to other groups of patients undergoing autografting. However, patients with chemotherapy refractory disease or with advanced stage at the time of diagnosis are unlikely to benefit from autografting, and efforts at stem cell mobilization may be hampered by administration of prior fludarabine, which is now nearly universal in the treatment of CLL [19]. Furthermore, with the recent introduction of combination regimens of chemo-immunotherapy showing excellent overall responses and prolonged disease-free survival in a subset of patients [3, 20], it is unclear at this time whether autografting holds any advantage over the current standard of care. Rising concerns over the growing incidence of myelodysplasia and AML in patients who received TBI-containing regimens has further dampened enthusiasm for autografting in CLL. In addition, in the Dana-Farber series 19% of autografted patients developed subsequent secondary malignancies [21]. As there has been no demonstration of a plateau and therefore no potential for this as a curative procedure, more groups have turned to investigations of allogeneic transplantation because of the demonstrated graft-versus-leukemia effect and greater potential for long-term disease control. Few investigators at this time are pursuing autologous transplant for CLL as part of clinical trials with novel interventions. Autologous transplant is not a treatment approach we consider for CLL patients outside of a well-designed clinical trial.

4.  Allogeneic Transplantation Using Myeloablative Conditioning Given the demonstrated responsiveness of CLL to increasing doses of chemotherapy and/or radiotherapy, initial studies of allogeneic transplantation for CLL focused on high-dose chemotherapy and/or radiotherapy-based regimens. The first of these reported by Bandini et al. in 1991 was a retrospective review of IBMTR data and case reports [22]. Of 26 patients identified,

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12 (46%) died of treatment-related mortality. However, at between 5 and 48 months 11 patients were alive and in clinical remissions. A retrospective cohort study looking at data from the EBMT and IBMTR found 54 patients with CLL who had undergone myeloablative conditioning and matched related donor bone marrow transplantation between the years of 1984 and 1992 [23]. Initial results from this study found that 38 patients (70%) at some point achieved a hematologic remission, with a 3-year probability of survival of 46%. Treatment-related mortality was significant at 46%. Michallet et al. updated this series in 2003 [24], providing the longest follow-up to date of myeloablative conditioning in CLL. This update showed encouraging results, and found that despite high early rates of treatment-related mortality, at 10 years of follow-up there was an overall survival of 41% with a disease-free survival of 36%. This was the first study to suggest a significant graft-versus-leukemia effect in CLL, given that no studies of autologous transplantation using similar conditioning regimens demonstrated a plateau in survival. Pavlitec et al. next reported a series of 23 patients in 2000 who had undergone high-dose therapy with either bone marrow or peripheral blood stem cell transplantation [25]. This series found that 87% of patients achieved a complete remission following transplantation, and at a median follow-up of 26 months 14 (61%) were alive and free of disease. The incidence of grades II–IV acute GVHD was 54%, and the day 100 mortality was 17% with a projected 5-year overall survival of 62%. Larger studies soon followed, with the largest study to date published in 2000 by Horowitz et al. for the IBMTR [26]. This was a registry study of 242 patients who underwent allografting using myeloablative regimens between 1990 and 1999. The majority of recipients received marrow products from HLA-identical siblings. This group of patients was compared to 83 CLL patients who underwent autografting using a similar conditioning regimen during the same time period. The authors found that 3-year survival probabilities were significantly higher in patients undergoing autografting (49 ± 8% vs. 87 ± 9%); however, deaths from disease progression were lower in allografted patients. Three-year progression-free survival was 44% after allografting, with younger patients with less advanced disease faring better. Later studies addressed specific questions in myeloablative allogeneic transplantation for CLL, such as the risk of using unrelated versus related donors and whether transplantation could overcome poor risk features. In 2005, Pavletic et  al. reported a registry study of 36 evaluable patients with CLL who underwent myeloablative conditioning followed by unrelated donor marrow transplantation [27]. This was a particularly high risk group of patients, with 55% being chemotherapy refractory at the time of transplantation, a variable previously shown to adversely impact the success of transplantation [28]. Twenty-one (58%) patients achieved a complete remission; however, interestingly in three of these patients delayed CR was noted, with one patient ultimately achieving a CR at 48 months after transplantation without other intervention, adding further evidence of a graft-versus-leukemia effect. However, at a median follow-up of 6 years only 29% of patients were alive and disease free. The estimated 5-year overall survival was 38%, owing in part to a 3-year treatment-related mortality of 38%. As anticipated with unrelated donor transplantation, rates of graft-versus-host disease were high, with grades III–IV acute GVHD of 29% and rates of limited and extensive stage chronic GVHD of 85%.

Chapter 4  Hematopoietic Progenitor Cell Transplantation for Treatment of CLL 

Myeloablative regimens with allogeneic transplantation have therefore been shown to lead to long-term disease-free survival, with a plateau in survival not observed with autologous transplantation. Thus, with this therapy there is true hope that CLL may be controlled long term via the graft-versus-leukemia effect. However, the prohibitive early treatment-related mortality related to toxicity from preparative regimens in addition to the higher rates of GVHD seen with myeloablative conditioning have lead to investigations of nonmyeloablative preparative regimens for use in this hematologic malignancy that usually affects older patients who are often heavily pretreated and have comorbid conditions.

5.  Allogeneic Transplantation Using Non-myeloablative Conditioning The demonstration of the graft-versus-leukemia (GvL) effect in CLL as well as the toxicity of myeloablative conditioning has prompted recent studies in the use of non-myeloablative conditioning regimens [29–33]. Recent publications of both prospective and retrospective analyses have shown encouraging results. The first prospective study was published in 2003 by Schetelig et al. who reported the results of NMA conditioning using fludarabine, busulfan, and antithymocyte globulin in 30 patients with CLL [29]. At a median follow-up of 2 years, the overall survival was 72% with a progression-free survival of 67% and treatment-related mortality of 15%. A subset of patients achieved molecular remissions. A larger study by Sorror et al. in 2005 examined 64 patients with CLL undergoing NMA conditioning and found an overall response rate of 67%, with a CR rate of 50%, and 2-year non-relapse mortality of 22%, again with a proportion of patients achieving molecular remissions [30]. Three prospective studies followed. Brown et al. examined 46 high risk patients who underwent NMA conditioning [31]. While 2-year treatment-related mortality was low at 17%, this study found a somewhat higher incidence of relapse and a lower overall survival than the previous studies, with 48% of patients progressing at 2 years and an overall survival of 54% at 2 years. An analysis of risk factors for relapse in this study found that chemotherapy refractory disease at the time of transplant, increasing percentage of bone marrow involvement, and an increased number of prior therapies all contributed to diminished progressionfree and overall survival. Khouri et  al. performed a prospective study of 39 patients using NMA conditioning, including patients with high risk features such as Zap-70 positivity and chemotherapy refractory disease [34]. This study estimated a 4-year overall survival of 48% with 4-year progression-free survival of 44%. Again, chemotherapy refractory disease was found to be a risk factor for relapse, as was mixed T-cell chimerism at day 90; however, other biologic risk factors did not affect relapse rates. Finally, Delgado et al. evaluated outcomes in 41 patients undergoing NMA conditioning and found a 2-year overall survival of 51% with an event-free survival of 45%. The overall survival in this study was diminished by post-transplantation viral and invasive fungal infections [33]. While no studies have been performed that randomize patients to standard myeloablative versus NMA conditioning regimens, Dreger et al. performed a retrospective EBMT analysis of 73 patients who underwent NMA conditioning

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compared with 82 patients from the EBMT database who received MA conditioning during the same time period [35]. This study found a significant reduction in treatment-related mortality in the NMA group but a higher incidence of relapse (hazard ratio 2.65). There was no significant difference in overall survival. Therefore, while allogeneic transplantation using NMA conditioning has been shown to result in encouraging rates of complete remissions (including molecular remissions), with decreased toxicity and overall lower treatmentrelated mortality, it is clear that optimal outcomes are observed in patients with chemotherapy-sensitive disease who undergo transplantation in optimal remission. In the case of chemotherapy refractory disease, consideration for standard myeloablative conditioning may lead to improved outcomes in the subgroup of patients with few comorbidities and good performance status, although definitive randomized studies are not available versus newer therapies.

6.  Allogeneic Transplantation and Genomic High Risk CLL In light of the inferior outcomes observed in CLL patients with high risk features treated with standard therapies, one of the more important questions in allogeneic transplantation for CLL has been whether the GvL effect is seen in high risk disease subtypes such as unmutated IgVH status, Zap-70 positivity, or high risk cytogenetic features. Moreno et  al. performed a retrospective study of allogeneic transplants performed at two centers which examined 23 patients who were either IgVH mutated or unmutated, compared with a group of 27 mutated and unmutated patients who underwent autologous stem cell transplantation [36]. Seven of the allogeneic transplant patients received non-myeloablative transplants. This study found that the risk of relapse was significantly higher for all patients following autologous transplantation than for the allogeneic transplant group (61% at 5 years vs. 12% at 5 years, respectively). Furthermore, survival was significantly longer in patients who underwent allogeneic transplantation. The relapse rate was significantly lower in unmutated patients who underwent allogeneic transplantation; however, these patients were not separated by type of conditioning regimen. As described previously, the study by Khouri et al. which specifically examined the effect of Zap-70 positivity and risk of relapse following NMA conditioning found that allogeneic transplantation was able to overcome this high risk feature [34]. Recently, preliminary data were presented by the EBMT regarding outcomes in patients with 17p deletions [37]. This was a retrospective study which identified 44 patients with 17p deletions who had undergone reduced intensity conditioning allogeneic transplantation. This study found that 4-year overall survival was 48%, with progression-free survival of 37%. Relapse related mortality was 36%, with non-relapse mortality of 27%. Sorror et  al. examined the long-term outcomes of patients with CLL who underwent allogeneic transplantation using reduced intensity conditioning regimens, giving specific attention to patients with adverse cytogenetics [38]. This study found that at a median follow-up of 5 years, the 65 patients who were transplanted had an overall response rate of 70%, with 55% complete remissions. The 5-year overall survival was 50%, with 5-year progression-free survival of 39%. Importantly, adverse cytogenetic risk factors were not found to increase the risk of relapse post-transplantation.

Chapter 4  Hematopoietic Progenitor Cell Transplantation for Treatment of CLL 

7.  Indications for Allogeneic Transplantation in CLL The optimal timing of allogeneic transplantation in CLL and recommendation for application of this therapy remain controversial. In the United States, the only published evidence-based consensus guidelines currently are the National Comprehensive Cancer Network (NCCN) Physician Guidelines, which recommend strong consideration for allogeneic transplantation for patients with del (17p13.1) who achieve a complete or partial response with induction chemotherapy, or in patients who have progressed following initial standard therapy (http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf). Most transplant centers use center-specific transplant criteria and regimens. Additional formal recommendations regarding transplantation were recently published by the European Bone Marrow Transplant Group (EBMT), who performed a literature review of available data [39]. Their recommendation for European practitioners suggested that allogeneic stem cell transplantation should be considered in patients who fail to respond or relapse early (within 12 months) following a purine nucleoside analog containing regimen, who relapse within 24 months of receiving a purine nucleoside analog containing regimen, or who have (del 17p13.1) abnormality requiring treatment. A similar analysis was published by the Italian Society of Hematology, who performed a systematic review of the literature for publication of evidence-based guidelines [40]. This group recommended that patients with CLL be considered for allogeneic transplantation if unfavorable biological risk factors are present, or for patients who demonstrate non-response or early relapse following purine analog-containing regimens. Performance of this therapy in these CLL patient populations is becoming more accepted as one standard option given evidence that this produces stable remissions with an extended plateau concurrent with acceptable long-term toxicity.

8.  Special Issues in Transplantation for CLL Chronic immunosuppression: Patients with CLL may have complications from their underlying disease during the peri-transplant period which are not shared by other hematologic malignancies. In particular, a high percentage of CLL patients will at some point in their disease course suffer from an autoimmune phenomenon such as autoimmune hemolytic anemia, immune thrombocytopenia, or autoimmune rheumatologic disease. In addition, the majority of patients will enter the transplantation process following periods of long-term immunosuppression due to both the underlying disease and the prior administration of highly immunosuppressive therapy used to treat the disease (purine nucleoside analogs, alemtuzumab). The risk of infection is exacerbated by the use of in  vivo T-cell depletion strategies for prevention of graftversus-host disease and by post-transplant immunosuppression. Thus, the transplanted CLL patient may be at risk for developing infections related to chronic neutropenia, impaired cellular immunity, and chronic hypogammaglobulinemia. Patients with persistent disease at the time of transplantation will have the additional risk of CLL-related impaired cellular immunity. The judicious use of prophylactic antimicrobial therapy, regular screening for CMV and EBV reactivation (if applicable), prophylaxis against invasive fungal infections if steroids are required, and monitoring immunoglobulin levels

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and supplementing hypogammaglobulinemia if necessary all may help to improve outcomes peri-transplantation. Donor selection: Donor selection in transplantation for CLL typically follows the standard genetic randomization of most transplants, in that if patients have an HLA-identical sibling they will receive a matched related donor transplant product. However, in light of the high incidence of familial CLL (up to 10% of all CLL patients will have a first-degree relative with CLL), sibling donors should undergo screening for CLL as part of the transplant evaluation. Peripheral blood flow cytometry will in most cases detect a monoclonal population of B-lymphocytes with a typical immunophenotype of CLL, eliminating that sibling as a potential donor. In light of recent improvements in managing graft-versus-host disease and the diminishing differences in adverse outcomes between sibling and unrelated donors, in this case an unrelated donor would be preferable and in fact might improve chances for long-term disease-free survival [38]. For those patients without a related or unrelated donor product, umbilical cord blood transplantation may be considered. However, at the present time there is little published data regarding the outcomes using umbilical cord blood products for transplantation in CLL, and this procedure would best be performed as part of a clinical trial. Choice of conditioning regimen: The majority of CLL patients transplanted at the present time receive NMA conditioning as a result of unacceptable treatment-related mortality using myeloablative conditioning. However, this choice may lead to inferior outcomes in patients with chemotherapy refractory disease, who have developed Richter’s (large cell) transformation, or who have bulky lymph node disease or extensive bone marrow infiltration. A retrospective study by MD Anderson found that the only patients with Richter’s transformation who achieved long-term disease-free survival were patients with chemosensitive disease who underwent myeloablative allogeneic transplantation [41]. More aggressive approaches may be required in these instances.

References 1. Xie Y, Davies SM, Xiang Y, Robison LL, Ross JA (2003) Trends in leukemia incidence and survival in the United States (1973–1998). Cancer 97:2229–2235 2. Byrd JC, Rai K, Peterson BL et al (2005) Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 105:49–53 3. Wierda WG, Kipps TJ, Keating MJ (2005) Novel immune-based treatment strategies for chronic lymphocytic leukemia. J Clin Oncol 23:6325–6332 4. Lamanna N, Kalaycio M, Maslak P et al (2006) Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol 24:1575–1581 5. Keating MJ, O’Brien S, Kontoyiannis D et  al (2002) Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma 43:1755–1762 6. Tam CS, O’Brien S, Lerner S et  al (2007) The natural history of fludarabinerefractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leuk Lymphoma 48:1931–1939 7. Damle RN, Wasil T, Fais F et  al (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847

Chapter 4  Hematopoietic Progenitor Cell Transplantation for Treatment of CLL  8. Montillo M, Hamblin T, Hallek M, Montserrat E, Morra E (2005) Chronic lymphocytic leukemia: novel prognostic factors and their relevance for riskadapted therapeutic strategies. Haematologica 90:391–399 9. Maloum K, Davi F, Merle-Beral H et  al (2000) Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia. Blood 96:377–379 10. Wiestner A, Rosenwald A, Barry TS et  al (2003) ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101:4944–4951 11. Del Poeta G, Maurillo L, Venditti A et  al (2001) Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood 98:2633–2639 12. Dohner H, Stilgenbauer S, Benner A et al (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916 13. Grever MR, Lucas DM, Dewald GW et  al (2007) Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol 25:799–804 14. Rabinowe SN, Soiffer RJ, Gribben JG et  al (1993) Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood 82:1366–1376 15. Provan D, Bartlett-Pandite L, Zwicky C et  al (1996) Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood 88:2228–2235 16. Gribben JG, Zahrieh D, Stephans K et  al (2005) Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood 106:4389–4396 17. Dreger P, Stilgenbauer S, Benner A et al (2004) The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a riskmatched analysis based on the VH gene mutational status. Blood 103:2850–2858 18. Michallet M, Chevret S, Brand R. Comparative study between autologous or allogeneic transplantations and conventional chemotherapy in chronic lymphocytic leukemia: A European Blood and Marrow Transplantation (EBMT) and French CLL Cooperative Group Study [abstract]. Bone Marrow Transplant. 2003 19. Laszlo D, Galieni P, Raspadori D et  al (2000) Fludarabine containing-regimens may adversely affect peripheral blood stem cell collection in low-grade non Hodgkin lymphoma patients. Leuk Lymphoma 37:157–161 20. Wierda W, O’Brien S, Faderl S et al (2006) A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer 106:337–345 21. Gribben JG (2007) Stem-cell transplantation in chronic lymphocytic leukaemia. Best Pract Res Clin Haematol 20:513–527 22. Bandini G, Michallet M, Rosti G, Tura S (1991) Bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant 7:251–253 23. Michallet M, Archimbaud E, Bandini G et al (1996) HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry. Ann Intern Med 124:311–315 24. Michallet M, Michallet AS, Le Q (2003) Conventional HLA-identical sibling bone marrow transplantation is able to cure chronic lymphocytic leukemia. A study from the EBMT and IBMT Registries [abstract]. Blood 102:474a 25. Pavletic ZS, Arrowsmith ER, Bierman PJ et  al (2000) Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 25:717–722 26. Horowitz M, Montserrat E, Sobocinski K (2000) Haematopoietic stem cell transplantation for chronic lymphocytic leukemia [abstract]. Blood 96:522a

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L.A. Andritsos et al. 27. Pavletic SZ, Khouri IF, Haagenson M et  al (2005) Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol 23:5788–5794 28. Khouri IF, Keating MJ, Saliba RM, Champlin RE (2002) Long-term followup of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4:217–221 29. Schetelig J, Thiede C, Bornhauser M et al (2003) Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 21:2747–2753 30. Sorror ML, Maris MB, Sandmaier BM et al (2005) Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 23:3819–3829 31. Brown JR, Kim HT, Li S et  al (2006) Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant 12:1056–1064 32. Khouri IF (2006) Reduced-intensity regimens in allogeneic stem-cell transplantation for non-hodgkin lymphoma and chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 390–397 33. Delgado J, Thomson K, Russell N et  al (2006) Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood 107:1724–1730 34. Khouri IF, Saliba RM, Admirand J et al (2007) Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol 137:355–363 35. Dreger P, Brand R, Milligan D et al (2005) Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 19:1029–1033 36. Moreno C, Villamor N, Colomer D et al (2005) Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 23:3433–3438 37. Schetelig J, van Biezen A, Caballero D et  al (2007) Allogeneic Hematopoietic cell transplantation for chronic lymphocytic leukemia (CLL) with 17p deletion: a retrospective EBMT analysis. ASH Annual Meeting Abstracts 110:47 38. Sorror ML, Storer B, Sandmaier BM et al (2007) Long-term follow up of patients (pts) with high-risk chronic lymphocytic leukemia (CLL) given nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). ASH Annual Meeting Abstracts 39. Dreger P, Corradini P, Kimby E et al (2007) Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 21:12–17 40. Brugiatelli M, Bandini G, Barosi G et  al (2006) Management of chronic lymphocytic leukemia: practice guidelines from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 91:1662–1673 41. Tsimberidou AM, O’Brien S, Khouri I et  al (2006) Clinical outcomes and prognostic factors in patients with Richter’s syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24:2343–2351

Chapter 5 The Role of Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia Patients in the Era of Tyrosine Kinase Inhibitors Richard T. Maziarz

When the history of hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) is reviewed, it is observed that the improved outcomes were a consequence of slow and incremental change over the years, as a result of prospective clinical trials or retrospective institutional or registry observations and analyses. This gradual progress of therapeutic advancement was an excellent demonstration of Darwinian evolution. Gould et al. have developed a novel evolution theory of “punctuated equilibrium,” in which periods of incremental change can be disrupted by sudden and sometimes cataclysmic events [1]. In the management of CML, the relatively sudden introduction of tyrosine kinase inhibitors (TKIs) into the disease management has led to saltatory evolutionary changes in which major paradigm shifts have taken place in the treatment of CML patients. In this chapter, we will review the results of HSCT for CML and also review the impact on standard transplantation with the emergence of imatinib and other kinase inhibitors, and how they have now redefined a new natural history for this leukemia. More importantly, with the near universal exposure of patients with CML to TKIs, it will be most critical to define when transplantation options should be pursued and offered to maintain the therapeutic goal of the best long-term outcome for patients with this disease.

1.  CML Pathogenesis, Clinical Features and Response Criteria CML is a clonal hematopoietic cell disorder with an annual incidence of 1–2 cases per 100,000 per year with a median onset in the fifth or sixth decade of life [2, 3]. It has three distinct clinical phases: a stable or chronic phase, followed by advanced phase disease, characterized as either accelerated phase or blast crisis. The chronic phase is characterized by a massive expansion of myeloid cells, usually with normal maturation features. In the more advanced From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_5, © Springer Science + Business Media, LLC 2003, 2010

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CML monitoring options CML Bone Marrow

Fluorescence in situ hybridization (FISH) for BCR-ABL Fusion

Metaphase Chromosome (Karyotype)

Bcr-Abl Quantitative Real-Time RT-PCR (LightCycler) Unknowns BCR-ABL

Ph(+)

G6PDH

PCR cycle PCR cycle Standard Curves (Known Copies), Quantification

normal

Fig.  5-1.  Mechanisms by which the disease burden of CML can be assessed: (a) bone marrow analysis, (b) karyotypic analysis, (c) FISH, (d) molecular analysis by reverse transcriptase-polymerase chain reaction.

phases, the leukemic cells lose their capacity to differentiate and can result in acute leukemia, i.e., “blast crisis” which is often highly refractory to standard chemotherapy. There is a hallmark cytogenetic abnormality known as the Philadelphia (PH) chromosome (Fig.  5-1). This cytogenetic abnormality is a shortened chromosome 22 seen by karyotypic analysis, which results from the reciprocal translocation between the long arms of chromosome 9 and 22. As a molecular consequence, there is a fusion of the C-Abl oncogene from chromosome 9 with chromosome 22 sequences within the breakpoint cluster region (BCR) resulting in the fused BCR-ABL gene. The gene product is the BCRABL tyrosine kinase, a constituitively active kinase that is considered to be the etiologic basis for CML. The fusion product leads to deregulated cellular proliferation, inhibition of apoptosis, genetic instability, and perturbation of the interaction of CML cells and the bone marrow stroma. CML is a stem cell disorder and, therefore, no standard chemotherapy agents or combination of agents were ever capable of eradicating this disease. Rather, for years, non-transplantation therapy for CML was focused on suppressing the proliferative phase with the hope of delaying the otherwise inevitable transformation to the accelerated and blast phases. Thus, non-transplantation management with chemotherapy, alpha interferon, or any other agent was focused at reduction of the burden of disease and this was best defined by reduction of the Ph+ marrow cells. Bone marrow cytogenetics were used to measure the response and classically, as defined by the NCCN, complete response was defined as the absence of Ph+ cells (0% Ph+), partial response was a reduction to < 36% (1–35%), and minor response was a

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation 

level of Ph+ cells between 36 and 95%. Persistence of >95% Ph+ cells was classified as no response [4]. Currently, molecular assessments with the quantitative polymerase chain reaction (qPCR) have become the standard monitoring tool for CML patients to determine levels of BCR-ABL transcripts with sensitivities of the assay several logs lower than assessable with cytogenetics. Molecular response measures include complete molecular response where BCR-ABL mRNA is undetectable by RT-PCR and major molecular response where there is a ³ 3 log reduction of BCR-ABL mRNA from baseline [4]. Ongoing monitoring is important to identify those patients who achieve the new goal of molecular remission as well as to identify those who develop early resistance [5].

2.  TKI and Other Targeted Therapy for CML There is no question that TKIs have emerged as the primary modality for treatment of CML patients [6–12]. The early phase I/II trials of imatinib mesylate (IM) demonstrated low toxicity despite the maximum tolerated dose never being reached with nearly 100% hematologic responses and over 50% cytogenetic remissions in patients with prior interferon resistance or intolerance. Advanced disease CML patients also demonstrated response although at lower rates compared to stable phase patients. In phase II trials of accelerated phase (CML-AP; n = 181), sustained hematologic responses and major cytogenetic responses to IM were found to be 69 and 24% respectively, with 17% complete cytogenetic responses identified [13]. In myeloid blast crisis CML (CML-BC; n = 229), IM responses were lower but still sustained hematologic responses in 31%, with major cytogenetic responses in 16%, of which 7% were complete [14]. However, only a small number of patients were available for long-term follow-up and only 18% of CML-AP and 3% of CML-BC patients maintained single agent IM on study. A clear dose--response effect emerged from these studies, with 600 mg showing superior response and survival advantage as opposed to 400 mg, the dose used in stable phase studies. However, IM at either dose was effective with low toxicity and served as a bridge to transplant for some and provided long-term remission to a small cohort of patients, particularly those in CML-AP. Overall survival estimates at 36 months for patients treated with 600 mg were 55% for CML-AP and 14% for CML-BC, and progression-free survival estimates were 40 and 7%, respectively [15]. These phase I and phase II studies rapidly led to phase III randomized, landmark study – International Randomized Study of Interferon vs. STI571 (IRIS) trial – comparing the interferon-based therapy with IM in the newly diagnosed chronic phase CML which proved that IM was the superior drug [9]. Recently, a 5-year update of the IRIS trial [8, 10] clearly demonstrated the ongoing superior survival in CML patients when they were treated with first-line IM, with an estimated 5-year survival in excess of 91% (even higher when scrutinized for CML-related deaths). What was quite unexpected was that the treatment response continued to improve with ongoing therapy. The likelihood of progression was highest in the first 2 years on TKI therapy, with the observed rate of progression per year lowest in years 4 and 5 (e.g., 7.5% rate of progression/year in year 2 vs. 1.5% in year 4) [10]. Additionally, for patients with a major molecular response at 12 months (currently, defined as > 3 log reduction in BCR-ABL from a standardized baseline), progression-free survival is 97% after 4.5 years, with no patients progressing to accelerated

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phase or blast crisis. Loss of response to IM could best predict the risk for relapse, and notably a good response to IM could override the stigma of having “higher risk” disease at the time of presentation, in contrast to patients treated with interferon [10, 16, 17]. The identification of patients with IM resistance, the elucidation of the resistance mechanisms, and the development of new targeted therapeutic agents have become the focus of intense CML investigation over the past half decade [11, 18–20]. Resistance is defined as primary (inability to achieve initial landmark responses) or secondary (those patients who achieved initial responses but subsequently lost hematologic or cytogenetic responses). In the latter condition, a large proportion of cases are demonstrated to have developed BCR-ABL kinase domain mutations, with clustering in the ATP binding loop (p-loop), the activation loop (a-loop), and at amino acid sites 315 and 351 of the molecule [11, 20]. The identification of these BCR-ABL mutations which confer resistance to IM have led to the development of a series of second-generation TKIs, including the recently FDA approved dasatinib and nilotinib [11, 21, 26]. Similar to IM, these agents have also rapidly demonstrated safety and efficacy in phase I and II trials, performed primarily in patients with imatinib resistance and intolerance with high percentages of major cytogenetic responses in patients with IM failure (although it is important to note that T315I mutations confer resistance to both of these agents) [27, 28]. Even major molecular responses (3-log or greater reduction in BCR-ABL transcripts) have been achieved in this IM-resistant CML patient population, although molecular remissions are more infrequent than seen in patients with primary disease. Research investigations continue to identify new small molecules with other molecular targets in CML patients that may ultimately be either substituted, for example the new aurora kinase inhibitors which appeared to target the mutated T315I BCR-ABL site, or potentially used in combination with the current group of TKI inhibitors [27]. However, in the background of these current investigations on BCR-ABL resistant CML, the potential application of allogeneic HSCT procedures remains relevant and critical to consider when one wishes to achieve the best long-term outcome for patients in this TKI era. To best appreciate the role of allogeneic HSCT for CML patients, it is appropriate to review its use in the past in the absence of available TKIs and as well as in the present, in this modern era of small molecule, targeted therapy.

3.  HSCT in the Pre-TKI Era HSCT had been the primary preferred target treatment for age-appropriate CML patients, based first and foremost on it being a highly curative modality. In contrast, only a minority of patients achieved long lasting responses with interferon-alpha, the main therapeutic agent in the era prior to the emergence of IM [29]. Some patients were rendered BCR-ABL negative, but few were able to maintain this status for years, and even in the best interferon responders, residual leukemic cells could be identified by RT-PCR. In contrast, using the immunotherapeutic maneuver of allografting, a great majority of patients gained and sustained molecular remission. Transplantation in the realm of conventional marrow ablative conditioning regimens was considered appropriate for young patients as well as for those who lacked medical co-morbidities. No clearly defined, absolute standard

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eligibility goals were ever demonstrated in clinical trials but many centers accepted human leukocyte antigen (HLA)-matched sibling donor HSCT for patients up to age 55–60 years with a slightly lower age being considered generally acceptable for unrelated HSCT. However, there was general recognition that these targets were influenced by additional factors such as co-morbid conditions, donor availability, disease stage (Fig.  5-2), sex and age shared between the donor and recipient, components of the “EBMT transplantation risk score” [29–34] (Table  5-1). Additionally, the traditional goal was to transplant patients within the first year of their disease, because single institutional

Fig.  5-2.  Probability of survival after unrelated HSCT for CML as determined by disease phase, 1998–2006. (Reproduced with permission of the CIBMTR and NMDP)

Table 5-1.  Overall survival according to EBMT transplantation risk score. Five-year overall survival (%) CIBMTR series Total risk score

EBMT series

All patients

ECP patients

0–1

72

69

70

2

62

63

67

3

48

44

50

4

40

26

29

5–7

22

11

25

All EBMT and CIBMTR patients were treated by conventional allo-HSCT procedures between 1989 and 1997. Leukemia-free survival (calculated only in the EBMT study) at 5 years was 61% for risk scores 0–1, 47% for risk score 2, 37% for risk score 3, 35% for risk score 4, and 19% for risk scores 5–7 This research was originally published in Blood. Ref. [90] © American Society of Hematology

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Fig.  5-3.  Probability of survival after related and unrelated HSCT for patients with CML in the first chronic phase, 1998–2004. (Reproduced with permission of the CIBMTR and NMDP)

studies as well as retrospective registry analyses provided evidence that early transplantation was associated with better outcomes [35] (Fig. 5-3). However, treatment related morbidity and mortality (TRM) associated with regimen related toxicity or graft versus host disease (GVHD) remained daunting and limiting for many patients. Additionally, it remained recognized that of all CML patients, only approximately 30% ever pursued sibling or unrelated HSCT; the other 70% were either too old or too infirm (45%), or had no suitable donors (25%) [36]. Regarding the history of CML transplantation, the first CML patient who underwent HSCT was one in the blast phase who underwent a single antigen mismatch, sibling donor HSCT. The patient engrafted, developed GVHD but unfortunately succumbed to CMV disease without evidence of leukemia [37]. This landmark event was the cornerstone that led to HSCT being the standard therapy for CML patients since the early 1980s, when the observations that the allograft procedure was associated with a graft versus leukemia (GVL) effect were made [38]. This was unfortunately and dramatically confirmed later in the 1980s when it was observed that CML patients experienced the highest relapse rates after T-cell depletion, confirming the critical importance of immune therapy in the management of this disease [39]. In 1991, Kolb et al. [40] confirmed the exquisite immune sensitivity of CML when they demonstrated that re-infusion of unstimulated donor T-cells in the absence of immune suppression was associated with both clinical responses and remissions in relapsed CML patients. Simultaneously, the Center for International Blood and Marrow Transplant Research (CIBMTR) performed a registry analysis that demonstrated that T-cell depleted HSCT actually led to lower PFS as syngeneic HSCT, as opposed to allogeneic HSCT, consistent with these other observations [39] (Table 5-2). Refinements in donor leukocyte infusions (DLI), either as sole therapy or in combination with TKI treatment, have continued to be made since this time [41–43]. In the 1990s, the

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation 

59

Table 5-2.  Relative risk of relapse for early leukemia after HSCT. ALL first CR Study group

N

AML first CR

CML CP

All patients

RR

P

N

RR

P

N

RR

P

N

RR

P

Allogeneic, non-T-depleted No GVHD59a

  90

1.00

–

228

1.00

–

115

1.00

–

433

1.00

–

Acute GVHD only

141

0.36

0.004

330

0.78

0.26

267

1.15

0.75

738

0.68

0.03

Chronic GVHD only

  28

0.44

0.16

  54

0.48

0.12

  45

0.28

0.16

127

0.43

0.01

Acute and chronic GVHD

  84

0.38

0.02

237

0.34

0.0003

164

0.24

0.03

485

0.33

0.0001

  12

0.99

0.99

  34

2.58

0.008

  24

2.95

0.08

  70

2.09

0.005

Syngeneic

Allogeneic, T-depleted   All patients

  84

1.20

0.61

163

1.30

0.33

154

5.14

0.0001

401

1.76

0.002

   No GVHD

  43

1.48

0.33

  83

1.57

0.12

  74

6.91

0.0001

200

2.14

0.0001

  Acute and/ or chronic GVHD

  41

0.98

0.97

  80

0.80

0.60

  80

4.45

0.003

201

1.32

0.25

a Reference group Relative risks are derived from multivariate Cox regression adjusting for Leukocyte count at diagnosis, recipient age, organ impairment pre-transplant, donor-recipient sex-match, and drug used to prevent GVHD RR relative risk in comparison with reference group, CR complete remission, CP chronic phase This research was originally published in Blood. Ref. [39] © American Society of Hematology

busulfan/cyclophosphamide preparative regimen became the standard regimen for conventional myeloablative transplantation for CML, when relapse rates were shown to be similar whereas regimen-related morbidity and mortality were lower when this regimen was compared with cyclophosphamide and total body irradiation (TBI) [44, 45]. This observation was not subsequently confirmed, when a study from France comparing these regimens did not demonstrate a negative impact of radiation exposure [45]. However, outcomes could be improved by pharmacokinetic monitoring of busulfan delivery, which allowed determination of steady-state concentrations that could be used to guide individualized dosing for an individual patient [46]. Further refinements with pharmacokinetic targeting were achieved with the use of intravenous busulfan, owing to its more dependable delivery, with which some investigators have reported improved long-term outcomes with the least treatment-related mortality (TRM) [47]. These latter advances have cemented the role of this preparative regimen for the disease. In the latter half of the 1990s, molecular matching for unrelated HSCT donors became standard. As molecular matching improved, the outcomes of patients undergoing unrelated HSCT also improved in parallel, such that the outcomes mimicked those in patients who received sibling allografts [48]. Most recently, comparative analyses of therapeutic efficacy of blood vs. marrow HSCT have been performed, demonstrating no clear advantage of either product in terms of overall survival, disease-free survival, non-relapse mortality, or acute and chronic GVHD [49]. Given the increasing recognition of the prolonged necessity for immunosuppression for chronic GVHD patients [50, 51], many centers are reverting to bone marrow harvests for CML patients or exploring other stem cell sources, for example, cord blood HSCT for CML patients [52].

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4.  HSCT in the Peri-TKI Era: The Emergence of Reduced Intensity Conditioning Regimens HSCT has continued to evolve over the past decade. Leading the advance has been reduced intensity and non-myeloablative HSCT (for review [53]). These approaches were developed to decrease the risk for transplant-related morbidity/ mortality in procedures conducted in older patients or those with co-morbid clinical conditions and, for younger patients desiring to preserve fertility. Excellent outcomes were reported in the earliest single institutional transplant studies in patients with CML [54–59]. Acceptable outcome results have been observed, albeit with relatively short follow-up. The Hadassah University team reported that progression free overall survival of 85% was achieved with a median follow-up of 37 months utilizing Fludarabine (150  mg/m2), Busulfan (8 mg/kg), and rabbit ATG (40 mg) [57]. GVHD remained an issue since 75% of the patients experienced clinical grade II–IV acute GVHD, and 55% experienced chronic GVHD. Similar outcomes were noted within the Fred Hutchinson Cancer Research Center (FHCRC) consortium using single dose 200 cGy TBI +/− Fludarabine 90 mg/m2 reduced intensity regimen. In this study [59], 24 CML patients were treated and with 36 month median follow-up, 13 were found to be alive in complete remission. TRM was 21%, and acute GVHD, grades II–IV were found in 50% of the patients. Additional studies with small number of patients, shorter follow-up and using varying intensity preparative regimens demonstrated projected 5-year survival ranging between 50 and 70%. One long-term retrospective analysis has also been reported by the investigators from the M.D. Anderson Cancer Center using their fludarabine-based reduced intensity HSCT procedures [60]. In 64 patients with advanced phase CML (80% beyond CP1), with a median follow-up of 7 years, the 5-year overall survival and progression-free survival were reported at 33 and 20%, respectively with TRM reported at 33, 39, and 48% at 100 days, 2 years, and 5 years, respectively. These data confirm that the reduced intensity HSCT can provide prolonged disease control, even in advanced phase CML, but more optimal approaches are needed for the management of patients not suitable for conventional HSCT, to achieve better long-term survivals [61]. Many similar studies have since been published or presented, but the largest retrospective analysis is the study reported by Crawley et al. [62] conducted in patients reported to the EBMT (Fig. 5-4). The assessment included a total of 211 CML patients, who were undergoing reduced intensity HSCT. The CML patient population was markedly heterogeneous with varying presenting disease states, multiple preparative regimens, and varying graft sources. Survival was found to be markedly influenced by the disease state. Overall survival for patients in the first chronic phase was 69%, in the second chronic phase was 57%, in accelerated phase was 24%, and in blast crisis was only 8%, mirroring experience with conventional allografts or other long-term single center analyses [30, 35, 61]. TRM was 9% at 1 year. Grades II–IV acute GVHD was seen in 33% of patients but only 10% experienced grade III–IV. Rejection was found at rates of 11% for this population of patients. In this retrospective analysis, the busulfan/fludaribine/antithymocyte globulin preparative regimen was associated with the best outcomes, with reduction in the TRM and improvement noted in disease-free survival [62].

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation 

Fig.  5-4.  Probability of overall and progression-free survival of patients with CML in all disease phases treated, undergoing sibling and unrelated donor reduced intensity HSCT. (This research was originally published in Blood. Ref. [62]. © The American Society of Hematology)

Based on these data, a proposal to the Blood and Marrow Transplant Clinical Trials Network for a randomized phase III trial of conventional myeloablative transplantation vs. reduced intensity transplantation in CML was submitted for consideration in patients aged 40–65 years (Maziarz and Druker, pers. comm.). The trial was not recommended for activation, however, because with the clear decline in allogeneic HSCT for CML in North America, it was believed that accrual targets would not be met in any reasonable time frame. In addition, despite excellent preliminary outcome data, there was a recognition that a longer follow up would be required before reduced intensity could truly emerge as a standard of care. Therefore, no randomized HSCT trial in CML is predicted to be forthcoming anytime soon; rather, we anticipate retrospective registry studies matching cohorts of CML patients receiving either reduced intensity or conventional HSCT will be performed [63]. These observations of a reduction in the HSCT procedures for CML were highlighted by the analysis of Giralt et  al. [64], who conducted a retrospective study of the CIBMTR database. Surprisingly, they demonstrated that the transplantation for CML was already declining before the US Food and Drug Administration approval of IM in 2001 (Fig. 5.5). At one time, CML was the number one malignancy for which unrelated transplants were performed; by 2005 it was the eighth most common hematologic disorder for which transplantation was offered, as indicated by the CIBMTR data and in the most recent updated CIBMTR statistics, only 2% of all unrelated transplantation procedures performed in 2007 was for CML patients. The analysis of the CIBMTR data pool conducted by Giralt et al. indicated that the greatest reduction in transplants was for CML patients in the first chronic phase, with the percentage change

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over 5 years ranging from 62 to 44% [64]. Additionally, 24% of patients were originally transplanted in the accelerated phase or second chronic phase, and this number had risen to 41% by 2005. HSCT for blast crisis remained relatively stable at 14–15%. Another trend noted was the marked increase in exposure to IM in CML patients undergoing HSCT, from 1% of CML patients registered in 1998 to 77% of patients registered with CIBMTR in 2003 (Fig. 5-6). It should be noted, however, that these changes in CML HSCT demographics may not be universal. The Latin American Cooperative Onco-Hematology Group [65] recently reported their experience in reduced intensity allogeneic HSCT, with over 95% survival in 24 patients at 28 months of follow up. Interestingly, they indicated that this may remain the optimal path for patients in their developing countries, because the median cost of allogeneic HSCT from days 0 through to 100 of transplantation was the same as 200 days of IM

Fig. 5-5.  The decline of HSCT procedures for CML in the peri-TKI era as documented by the CIBMTR. (Reproduced from [64]. © 2007 CIBMTR. © 2007 Blackwell Publishing Ltd)

Fig.  5-6.  Increased exposure to imatinib prior to HSCT. (Reproduced from [64]. © 2007 CIBMTR. © 2007 Blackwell Publishing Ltd)

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation 

prescribed at 400 mg/day. A follow-up analysis, in Mexico, only compared 22 patients who underwent reduced intensity HSCT with a comparable group of 50 patients treated with TKI, primarily IM [66]. Six year overall survival after HSCT vs. TKI for PH + CML was 77 and 84%, respectively (p = NS), with the additional observation that freedom from progression to advance phases was similar in both groups. The authors highlight the fact that the median cost of each reduced intensity HSCT was US $18,000, an amount comparable to one hundred days of treatment of IM at 400 mg per day. This raises the concern that although the initial costs of allogeneic HSCT are higher, the lifetime treatment with expensive pharmaceuticals may actually place the greatest burden on resources. The same observation was also made in Europe, where it was suggested that the costs of reduced intensity HSCT became less expensive than IM within 2 years of the procedure [67]. These policy issues will continue to be highlighted, particularly in young patients in whom the greatest advantage of allogeneic transplantation can be gained as TRM is the lowest vs. potentially decades of continued drug therapy and its projected concomitant costs.

5.  HSCT in the Post-TKI Era: Does Early HSCT Provide Optimal Outcomes? Advances in allogeneic HSCT for CML continue with close scrutiny on where TKI and transplant therapies interact and intersect. Major questions that persist include assessing the impact on pre- and post-transplant TKI therapy, optimal donor source, monitoring, and decision-making regarding the management of relapse with either DLI, imatinib, or both. One of the most highly discussed issues currently is the management of the young patient with CML [68]. Despite the excellent data presented in the IRIS trial, some physicians still suggest that, in the absence of long-term data with IM, young patients with sibling donors should still consider proceeding to allogeneic HSCT. These recommendations have been based on prior retrospective analyses suggesting that HSCT during the first year of diagnosis was associated with better outcomes, and a lack of clear data, suggesting that pre-transplant IM would not enhance treatment-related morbidity and mortality. Hehlmann et al. [69] have now demonstrated that there is no benefit from early allogeneic HSCT with sibling donors in patients with CML. The German CML transplantation group conducted the first ever randomized prospective trial of early HSCT vs. best available therapy. This trial began in the interferon era in 1995, and all new, age-appropriate CML patients were enrolled (including children; youngest was age 11 years, accounting for about 4% of HSCT-eligible patients). If they had an HLA-matched sibling, they proceeded to early transplantation, but if not, then the patient received interferon-based therapy with unrelated HSCT used for salvage. This study clearly demonstrated a survival benefit for patients who were treated with interferon-based therapy over early transplantation. Additionally, the transplant risks were even more pronounced for CML patients with low risk disease on presentation with 4 year survival at 91% for the nontreatment arm vs. 66% for the HSCT arm. Clearly, TRM rates of 29% in the transplant arm influenced these data, but the conclusions were clear; HSCT was best utilized later in the CML disease course rather than within the first year of diagnosis.

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6.  HSCT in the Post-TKI Era: Does Pre-Transplant TKI Exposure Impact HSCT Outcomes? It is important to appreciate that to date there is no clear evidence to suggest that pre-transplant IM or other TKIs will negatively influence the outcome of patients undergoing future transplantation. Most studies reported on this issue included very small patient numbers [70–73]. For example, Zaucha et al. [70] reported 30 patients with PH+ leukemias who experienced no increased hepatic toxicity, graft-versus-host disease, or 100-day mortality when compared with historic control individuals. Deininger et al. presented the EBMT series of 70 patients with advanced PH+ disease [74], in which no impact on engraftment, TRM, graft-versus-host disease, or relapse was observed in patients pre-treated with IM. Most importantly, pre-transplant disease control was most predictive of superior outcomes. Finally, Lee et al. have reported the largest experience to date, mostly of patients who proceeded to HSCT after IM therapy administered mostly for interferon resistance and/or intolerance [75]. An analysis was performed on 409 CML patients transplanted either in the first chronic phase or beyond the first chronic phase, and was compared to 900 CML patients who had not received prior IM. Among patients in the first chronic phase, IM pre-HSCT therapy was associated with improved survival but no statistically significant difference in TRM, relapse, or leukemia-free survival (LFS) was observed. A matched pair analysis of this cohort was performed and supported the observation that there was a higher survival rate among first chronic phase patients. In patients with advanced disease, use of IM before HSCT was not associated with increased TRM, relapse, LFS, or overall survival. Similar observations are now being reported for HSCT after pre-transplant nilotinib and dasatinib exposure [73]. Thus, when all these data are taken together, there appears to be no clinical reason why CML patients should not receive upfront TKI therapy, even if they are HSCT eligible. Theoretically, TKI pre-treatment may decrease the tumor burden, thus allowing maximal time for the adaptation of the donor immune system and improvement of the ultimate goal of obtaining a graft vs. leukemia effect. Advanced phase patients remain at risk for worse outcomes, often due to higher relapse rates but as well, due to ongoing increased risks of transplant-related mortality [61, 74, 75]. For the non-advanced phase patients, it remains to be determined if worse outcomes are obtained by proceeding to HSCT after failure of TKI although at least one study makes the important observation that BCR-ABL mutation status does not confer resistance to the immune therapeutic manuever of an allograft [76, 77].

7.  HSCT in the Post-TKI Era: TKI Therapy in the Post Allograft Setting The use of TKIs after HSCT is also under scrutiny. Recent reports from the Hammersmith Hospital group have highlighted the need for ongoing molecular monitoring of CML patients. In 243 patients who underwent allogeneic HSCT for CML, long-term monitoring using RT-PCR (median follow up 84.3 months) revealed four categories of patients: (1) 129 patients with molecular or cytogenetic relapse, (2) 27 patients with persistently positive, low-level BCR -ABL signals but never more than three consecutive positive results, (3)

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation 

51 patients with fluctuating positive, low-level signal with never more than two consecutive positive results, and (4) only 36 patients were characterized as persistently negative or with the single low-level positive result [78, 79]. Additionally, a CIBMTR analysis of long-term outcome of allogeneic HSCT for CML has been performed; 2234 patients were identified as alive in remission of 5 years post-allogeneic HSCT. It was identified after 5 years that there was a low but constant relapse rate that persisted for over 15 years and that 22% of the deaths occurring after 5 years from HSCT were CML-related deaths [80]. These long-term observations certainly support the efforts of CML transplant teams to further explore the post-allograft prophylaxis or therapeutic interventions for CML relapse with TKIs. In these circumstances, multiple groups have shown that IM for CML relapse after HSCT can successfully be used for treatment [81–85] and as well can be combined with therapeutic DLI (Fig. 5-5) [86, 87]. What is likely to become more widely incorporated will be the use of TKIs as post-HSCT adjuvant therapy for prophylaxis against relapse, while awaiting the establishment of full engraftment and full donor lymphoid chimerism. In this setting, several centers have shown that IM can be used safely from approximately 1 month after HSCT until beyond 1 year, with therapeutic efficacy in control of relapse [88, 89] (Fig. 5-7).

Fig. 5-7.  The use of imatinib may potentiate DLI in the management of CML relapse after allogeneic HSCT. (Reprinted by permission from Macmillian Publishers Ltd: Ref. [86], © 2005)

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8.  Who Should Receive Transplantation for CML in the IM Era? So which patients with CML should be considered for transplantation in 2008? It is expected that, primarily, patients with either advanced disease or with IM resistance will be considered for HSCT at least in those countries where TKI therapy is available (see Table  5-3 for definitions of TKI treatment failure and suboptimal primary response) [4, 11, 12, 18–20, 90]. Clearly, the degree of primary or secondary resistance that is encountered will influence patients as well as their treating physicians regarding how quickly to proceed. What is accepted universally is that the lack of complete hematologic response at 3 months, a lack of a major cytogenetic response at 12 months, or a lack of a complete cytogenetic response by 18 months are findings felt to be consistent with IM failure [4, 90]. Additionally, patients with cytogenetic progression or relapse and certainly those with hematologic relapse or even “sudden blast crisis” [91] while receiving IM, will be candidates for HSCT as well as for consideration for second-generation TKI therapy [4, 11, 12, 19–26, 90]. Longterm data on these agents are needed, however, to determine their ability to provide long-term salvage. Thus, given the unknown duration of response, these are the situations for CML patients when HSCT becomes relevant and should be considered. Not all patients will elect to pursue HSCT, being cognizant of experience with first-line IM and because of reluctance to accept the uncertainty of outcomes with HSCT, but defining the transplant options becomes important Table 5-3.  Operational definition of failure and suboptimal response for previously untreated patients in ECP CML who are treated with 400 mg IM daily. Time

Failure

Suboptimal response Warnings

Diagnosis

NA

NA

3 months after diagnosis

No HR (stable disease or disease progression)

Less than CHR

6 months after diagnosis

Less than CHR, no CgR (Ph+ > 95%)

Less than PCgR (Ph+ > 35%)

NA

12 months after diagnosis

Less than PCgR (Ph+ > 35%)

Less than CCgR

Less than MMolR

18 months after diagnosis

Less than CCgR

Less than MMolR

NA

Anytime

Loss of CHRa, loss of CCgRb, mutationc

ACA in Ph+ cellsd, loss of MMolRd, mutatione

Any rise in transcript level; other chromosome abnormalities in Ph- cells

a

High risk, del9q+, ACAs in Ph+ cells NA

To be confirmed on two occasions unless associated with progression to AP/BC To be confirmed on two occasions, unless associated with CHR loss or progression to AP/BC c High level of insensitivity to IM d To be confirmed on two occasions, unless associated with CHR or CCgR loss e Low level of insensitivity to IM Failure implies that the patient should be moved to other treatments whenever available. Suboptimal response implies that the patient may still have a substantial benefit from continuing IM treatment but that the long-term outcome is not likely to be optimal, so the patient becomes eligible for other treatments. Warnings imply that the patient should be monitored very carefully and may become eligible for other treatments. The same definitions can be used to define the response after IM dose escalation PCgR indicates partial CgR; and NA, not applicable This research was originally published in Blood. Ref. [90] © American Society of Hematology b

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation 

Table 5-4.  An institutional perspective of CML patients and indications for hematopoietic stem cell transplantation: 2008. Phase

Clinical setting

CP1

Primary hematologic failure to IM therapy

CP1

Primary cytogenetic failure to IM therapy

CP1

Progression after primary imatinib therapy

CP1

Imatinib resistant, mutations at BCR-ABL 315 locus

CP1

Imatinib resistant, partial response to second-generation inhibitors

CP1

Intolerance to tyrosine kinase inhibitors

CP1

Clonal evolution, in setting of TKI resistance

CP1

Outgrowth of alternate Philadelphia-negative cytogenetically abnormal clones with myelodysplasia

AP

New diagnosis, after primary imatinib therapy, in patients with low EBMT score

AP

Imatinib responsive but later progression in patients with high EBMT score

BC

After induction with TKI ± combination chemotherapy

AP accelerated phase, BC blast crisis, CP1 first chronic phase, EBMT European Group for blood and marrow transplantation

[90]. In the first chronic phase, at our institution, potential HSCT scenarios are reviewed and considered for patients with primary hematologic or cytogenetic failure to IM therapy, as well in those with progressive disease (see Table 5-4). Described mechanisms of resistance such as tyrosine kinase mutations are more frequent in patients with secondary failure, and thus the concern is that over time such “unstable” clonal disease may evolve further and evade salvage options as well, thus warranting HSCT after re-establishing control in such patients [77]. A small number of patients are intolerant of IM and can be considered for second-generation TKI therapy with transplantation at progression. Clearly, patients who are resistant to IM and exhibiting a partial response only to second-generation TKI treatment must consider HSCT, particularly if they are young and have excellent matched options, either sibling or unrelated donor. Finally, there are some circumstances for which most patients are not monitored that would influence the decision to pursue HSCT. These include the identification of mutations at the 315 site of BCR-ABL, which are universally associated with resistance to the known first-generation and second-generation TKIs [27, 28]. Novel kinase inhibitors are being tested in clinical trials that target this particular mutant BCR-ABL site. Our policy, as in many centers, is to offer HSCT to CML patients with T315I mutations, either directly or after being treated in a clinical trial. Finally, there are relatively uncommon circumstances for consideration for HSCT when early clonal evolution is seen in patients failing IM [92] or when myelodysplasia is found in patients with TKI-induced PH– hematopoiesis [93]. For patients with advanced phase CML, early transplantation for accelerated phase patients is considered, but preferably for those with lower EBMT scores (see Table 5-2 for HSCT outcomes impacted by the EBMT score) [34]. For those patients who are in an accelerated phase with significant co-morbid conditions or with a high EBMT score, transplant options are outlined, but alternatively, one may choose to closely monitor the TKI failure before pursuing

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HSCT in those patients. For patients with blast crisis who are age eligible, HSCT is universally recommended after disease control is achieved, generally by induction chemotherapy in combination with IM or another TKI. The transplant community recognizes that these considerations will change. As new agents are developed, for instance those that may overcome the resistance associated with BCR/ABL T315I mutations, it will create circumstances where management algorithms will also evolve. Certainly, there are questions that remain that have attracted significant attention without clear answers or without clear agreement of the transplant community such as the role of transplantation in the very young patient with CML. We all hope and expect that the role of small molecule targeted therapy may impact and change the natural history of many malignancies. Certainly, there has been a dramatic alteration in the treatment strategies and improvement in clinical outcomes in adults with Ph+ ALL (rev in [94]). Early HSCT still remains the primary goal in this setting in adults, but IM therapy has entered all aspects of management from primary treatment to long-term maintenance, and appears to have changed the natural history with markedly improved PFS and OS reported. But, even in this clinical setting which had been universally considered a non-debatable indication for HSCT in the ageappropriate patient, novel trials are being considered within the United States to compare HSCT in CR1 to primary therapy with second-generation TKIs alone.

9.  Conclusions HSCT is a complex and morbid procedure that requires significant resources and technical skills in those whom perform it. The advent of molecular targeted therapy for CML has led to the dramatic decline in HSCT procedures, but the need remains for HSCT for patients who fail TKI therapies or who present with more aggressive disease. In the interim, ongoing advances in HSCT research may continue to improve outcomes for CML patients either by (a) decreasing transplant-related mortality, perhaps by the development of novel conditioning regimens [95] or developing technologies to identify those at highest risk of organ damage [96] or (b) by determining novel means to reduce relapse rates, for example by optimizing natural killer cell grafts [97] or by using selected tumor-specific, vaccine strategies [98]. Alternatively, autologous HSCT may reemerge in therapeutic algorithms, given the ability to collect large numbers of PH– peripheral blood stem cells [99–101]. Currently, one fact that we do know is that the future of HSCT for CML will change and will be determined by clinical investigations of novel therapeutics with close attention to the economics of cancer care, and it will be interesting to observe in this current age of cellular and regeneration therapy whether HSCT for CML takes the path of the Irish Elk toward extinction [102] or evolves dramatically and adapts to become more functional, similar to the development of the Panda’s thumb [103].

References 1. Gould SJ (2002) The structure of evolutionary theory. Harvard University Press, Cambridge 2. Hehlmann R, Hochhaus A, Baccarani M et al (2007) Chronic myeloid leukaemia. Lancet 370 (9584):342–350 3. Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105(7):2640–2653

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation  4. National Comprehensive Cancer Network (2008) "NCCN Clinical Practice Guidelines in Oncology," Chronic Myelogenous Leukemia. http://www.nccn.org/ professionals/physician_gls/PDF/cml.pdf Accessed July 14, 2008 5. Sahay T, Schiffer CA (2008) Monitoring minimal residual disease in patients with chronic myeloid leukemia after treatment with tyrosine kinase inhibitors. Curr Opin Hematol 15(2):134–139 6. Druker BJ, Talpaz M, Resta DJ et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Eng J Med 344(14):1031–1037 7. Kantarjian H, Sawyers C, Hochhaus A et al (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Eng J Med 346(9):645–652 8. Hochhaus A, Druker B, Sawyers C et al (2008) Favorable long-term follow-up results over six years for response, survival and safety with imatinib mesylate therapy in chronic phase chronic myeloid leukemia post failure of interferonalpha treatment. Blood 111(3):1039–1043 9. O'Brien SG, Guilhot F, Larson RA et al (2003) IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase myeloid leukemia. N Engl J Med 348(11):994–1004 10. Druker BJ, Guilhot F, O'Brien SE et al (2006) Five-year follow-up of imatinib therapy for newly diagnosed chronic leukemia in chronic-phase shows sustained responses and high overall survival. N Engl J Med 355(23): 2408–2417 11. Ramirez P, DiPersion JF (2008) Therapy options in Imatinib failures. The Oncologist 13(4):424–434 12. Mauro MJ, Heinrich MC (2008) Treatment of chronic myeloid leukemia with BCRABL kinase inhibitors. Innovative Leukemia and Lymphoma Therapy. Kaspers GJL, Coiffier B, Heinrich MC, Estety E (eds) Informa Healthcare, New York 13. Talpaz M, Silver RT, Druker BJ et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase II study. Blood 99(6):1928–1937 14. Sawyers CL, Hochhaus A, Feldman E et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99(10):3530–3539 15. Talpaz M, Goldman JM, Sawyers CL et al (2003) High dose imatinib (ST1571, Gleevec) provides durable long-term outcomes for patients (pts) with chronic myeloid leukemia (CML) in accelerated phase (AP) or myeloid blast crisis (BC): Follow-up of the phase II studies. Blood 102(11):905a 16. Sokal JE, Cox EB, Baccarani M et al (1984) Prognostic discrimination in “goodrisk” chronic granulocytic leukemia. Blood 63(4):789–799 17. Hasford J, Pfirrmann M, Hehlmann R et al (1998) A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon-alpha. J Nat Cancer Inst 90(11):850–858 18. O'Hare T, Eide CA, Deininger MW (2007) BCR-ABL kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110(7):2242–2249 19. Shah NP, Tran C, Lee FY et al (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305(5682):399–401 20. Mauro MJ (2006) Defining and managing imatinib resistance. Hematology Am Soc Hematol Educ Program 219–225 21. Kantarjian H, Pasquini R, Hamerschlak N et al (2007) Dasatinib or high-dose imatinib for chronic-phase myeloid leukemia after failure of first-line imatinib: a randomized phase II trial. Blood 109(7):5143–5150 22. Talpaz M, Shah NP, Kantarjian H et al (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Eng J Med 354(24):2531–2541

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70 

R.T. Maziarz 23. Guilhot F, Apperley J, Kim DW et al (2007) Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or intolerant chronic myeloid leukemia in accelerated phase. Blood 109(10):4143–4150 24. Cortes J, Rousselot P, Kim DW et al (2007) Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or intolerant chronic myeloid leukemia in blast crisis. Blood 109(8)3207–3213 25. Kantarjian HM, Giles F, Gattermann N et al (2007) Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110(10):3540–3546 26. Hochhaus A, Kantarjian HM, Baccarani M et al (2007) Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109(6):2303–2309 27. Giles FJ, Cortes J, Jones D et al (2007) MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109(2):500–502 28. Nicolini FE, Hayette S, Corm S et al (2007) Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring at T315I BCR-ABL mutation. Haematologica 92(9):1238–1241 29. Chronic Myeloid Leukemia Trialists' Collaborative Group (1997) Interferon alpha versus chemotherapy for chronic myeloid leukemia: A meta-analysis of seven randomized trials. J Natl Cancer Inst 89(21):1616–1620 30. Apperely JF (2006) Managing the patient with chronic myeloid leukemia through and after allogeneic stem cell transplantation. Hematology Am Soc Hematol Educ Program 226–232 31. Gratwohl A, Brand R, Apperely J et al (2006) Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: Transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 91(4):513–521 32. Robin M, Guardiola P, Devergie A et al (2005) A 10-year median follow-up study after allogeneic stem cell transplantation for chronic myeloid leukemia in chronic phase from HLA-identical sibling donors. Leukemia 19(9):1613–1620 33. Goldman JM (2007) How I treat chronic myeloid leukemia in the imatinib era. Blood 110(8):2828–2837 34. Gratwohl A, Hermans J, Goldman JM et al (1998) Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 352(9134):1087–1092 35. Horowitz MM, Rowlings PA, Passweg JR (1996) Allogeneic bone marrow transplantation for CML: A report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant 17(Suppl 3):55–56 36. Goldman JM (2001) “Stem cell transplantation for CML: Its place in treatment algorithms 2001” in Chronic Myelogenous Leukemia." Hematology 103–112 37. Buckner CD, Epstein RB, Rudolph RH et al (1970) Allogeneic marrow engraftment following whole body irradiation in a patient with leukemia. Blood 35(6):741–750 38. Weiden PL, Flournoy N, Thomas ED et al (1979) Antileukemic effect of graftversus-host disease in human receipients of allogeneic-marrow grafts. N Eng J Med 300(19):1068–1073 39. Horowitz MM, Gale RP, Sondel PM et al (1990) Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75(3):555–562 40. Kolb HJ, Mittermuller J, Clemm C et al (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76(12):2462–2465

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation  41. Guglielmi C, Arcese W, Dazzi F et al (2002) Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood 100(2):397–405 42. Weisser M, Tischer J, Schnittger S et al (2006) A comparison of donor leukocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who relapsed after allogeneic stem cell transplantation. Haematologica 91(5):663–666 43. Traversari C, Marktel S, Magnani Z et al (2007) The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies. Blood 109(11):4708–4715 44. Clift RA, Buckner CD, Thomas ED et al (1994) Marrow transplantation for chronic myeloid leukemia: A randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 84(6):2036–2043 45. Devergie A, Blaise D, Attal M et al (1995) Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busuifan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SGM). Blood 85(6):2263–2268 46. Slattery JT, Clift RA, Buckner CD et al (1997) Marrow transplantation for chronic myeloid leukemia: The influence of plasma busulfan levels on the outcome of transplantation. Blood 89(8):3055–3060 47. Thall PF, Champlin RE, andersson BS (2004) comparison of 100-day mortality rates associated with i.v. busulfan and cyclophosphamide vs other preparative regimens in allogeneic bone marrow transplantation for chronic myelogenous leukemia: Bayesian sensitivity analyses of confounded treatment and center effects. Bone Marrow Transplant 33(12):1191–1199 48. Hansen JA, Gooley TA, Martin PJ et al (1998) Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338(14):962–968 49. Oehler VG, Radich JP, Storer B et al (2005) Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia. Bio Blood Marrow Transplant 11(2):85–92 50. Stewart BL, Storer B, Storek J et al (2004) Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood 104(12):3501–3506 51. Eapen M, Logan BR, Confer DL et al (2007) Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graftversus-host disease without increased survival. Bio Blood Marrow Transplant 13(12):1461–1468 52. Nagamura-Inoue T, Kai S, Azuma H et al (2008) Unrelated cord blood transplantation in CML: Japan Cord Blood Bank Network analysis. Bone Marrow Transplant 42(4):241–251 53. Scott BL, Sandmeier BM (2006) Outcomes with myeloid malignancies. Hematology Am Soc Hematol Educ Program 381–389 54. Slavin S, Nagler A, Naparstek E et al (1998) Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91(3):756–763 55. Bornhauser M, Kiehl M, Siegert W et al (2001) Dose-reduced conditioning for allografting in 44 patients with chronic myeloid leukemia: a retrospective ­analysis. Br J Haematol 115(1):119–124 56. Das M, Saikia TK, Advani SH et al (2003) Use of a reduced-intensity conditioning regimen for allogeneic transplantation in patients with chronic myeloid leukemia. Bone Marrow Transplant 32(2):125–129

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R.T. Maziarz 57. Or R, Shapira MY, Resnick I et al (2003) Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in the first chronic phase. Blood 101(2):441–445 58. Okamoto S, Watanabe R, Takahaski S et al (2002) Long-term follow-up of allogeneic bone marrow transplantation after reduced-intensity conditioning in patients with chronic myelogenous leukemia in the chronic phase. Int J Hematol 75(7):493 59. Kerbauy FR, Storb R, Hegenbart U et al (2005) Hematopoietic cell transplantation from HLA-identical sibling donors after low-dose radiation-based conditioning for treatment of CML. Leukemia 19(6):990–997 60. Kebriaei P, Detry MA, Giralt S et al (2007) Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood 110(9):3456–3462 61. Bornhauser M, Kroger N, Schwerdtfeger R et al (2006) Allogeneic haematopoietic cell transplantation for chronic myelogenous leukaemia in the era of imatinib: a retrospective multicentre study. Eur J Haematol 76(1):9–17 62. Crawley C, Szydlo R, Lalancette M et al (2005) Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic ­factors from the Chronic Leukemia Working Party of the EBMT. Blood 106(9): 2969–2976 63. Faber E, Koza V, Vitek A et al (2007) Reduced-intensity conditioning for allogeneic stem cell transplantation in patients with chronic myeloid leukemia is associated with better overall survival but inferior disease-free survival when compared with myeloablative conditioning – a retrospective study of the Czech National Hematopoietic Stem Cell Transplantation Registry. Neoplasma 54(5):443–444 64. Giralt SA, Arora M, Goldman JM et al (2007) Impact of imatinib therapy on the use of allogeneic haematopoietic progenitor cell transplantation for the treatment of chronic myeloid leukaemia. Br J Haematol 137(5):461–467 65. Ruiz-Arguelles GJ, Gomez-Almaguer D et al (2005) the early referral for reduced-intensity stem cell transplantation in patients with PH1(+) chronic myelogenous leukemia in chronic phase in the imatinib era: results of the Latin American Cooperative Oncohematolgoy Group (LACOHG) prospective, multicenter study. Bone Marrow Transplant 36(12):1043–1047 66. Ruiz-Arguelles GJ, Tarin-Arzaga LC, Gonzalez-Carrillo ML et al (2008) Therapeutic choices in patients with PH-positive CML living in Mexico in the tyrosine kinase inhibitor era: SCT or TKIs? Bone Marrow Transplant 42(1): 23–28 67. Krejci M, Mayer J, Doubek M et al (2006) Clinical outcomes and direct hospital costs of reduced-intensity allogeneic transplant 38(7):483–491 68. Millot F, Guilhot J, Nelken B et al Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia 20(2):187–192 69. Hehlmann R, Berger U, Pfirrmann M et al (2007) Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 109(11):4686–4692 70. Zaucha JM, Prejzner W, Giebel S et al (2005) Imatinib therapy prior to myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 36(5): 417–424 71. Shimoni A, Kroger N, Zander AR et al (2003) Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemia. Leukemia 17(2):290–297 72. Oehler VG, Gooley T, Snyder DS et al (2007) The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood 109(4):1782–1789

Chapter 5  The Role of Allogeneic Hematopoietic Stem Cell Transplantation  73. Jabbour E, Cortes J, Kantarijian H et al (2007) Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity. Cancer 110(2):340–344 74. Deininger M, Schleuning M, Greinix H et al (2006) The effect of prior exposure to imatinib on transplant-related mortality. Haematologica 91(4):452–459 75. Lee SJ, Kukreja M, Wang T et al (2008) Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood 112(8):3500–3507 76. Weisser M, Schmid C, Schoch C et al (2005) Resistance to pretransplant imatinib therapy may adversely affect the outcome of allogeneic stem cell transplantation in CML. Bone Marrow Transplant 36(11):1017–1018 77. Jabbour E, Cortes J, Kantarjian HM et al (2006) Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after BCR-ABL kinase mutation-related imatinib failure. Blood 108(4): 1421–1423 78. Marin D, Kaeda J, Szydlo R et al (2005) Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: patterns of residual leukaemia and prognostic factors for cytogenetic relapse. Leukemia 19(4):507–512 79. Kaeda J, O'Shea D, Szydlo RM et al (2006) Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107(10):4171–4176 80. Goldman JM, Sobocinski KA, Zhang MJ et al (2006) Long-term outcome after allogeneic hematopoietic cell transplantation (HCT) for CML. Bio Blood Marrow Transpl 12(2):17 81. Olavarria E, Ottmann OG, Deininger M et al (2003) Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 17(9):1707–1712 82. Kantarjian HM, O'Brien S, Cortes JE et al (2002) Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 100(5):1590–1595 83. DeAngelo DJ, Hochberg EP, Alyea EP et al (2004) Extended follow-up of patients treated with imatinib mesylate (Gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: during cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res 10(15):5065–5071 84. Ullmann AJ, Hess G, Kolbe K et al (2003) Current result of the use of imatinib mesylate in patients with relapsed Philadelphia chromosome positive leukemia after allogeneic or syngeneic hematopoietic stem cell transplantation. Keio J Med 52(3):182–188 85. Kim YJ, Kim DW, Lee S et al (2004) Cytogenetic clonal evolution alone in CML relapse post-transplantation does not adversely affect response to imatinib mesylate treatment. Bone Marrow Transplant 33(3):237–242 86. Savani BN, Montero A, Kurlander R et al (2005) Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation. Bone Marrow Transplant 36(11): 1009–1015 87. Simula MP, Markel S, Fozza C et al (2007) Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia 21(9):943–948 88. Carpenter PA, Snyder DS, Flowers ME et al (2007) Prophylactic administration of imatinib after hematopoietic stem cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 109(7):2791–2793

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R.T. Maziarz 89. Olavarria E, Siddique S, Griffiths MJ et al (2007) Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia. Blood 110(13):4614–4617 90. Baccarani M, Saglio G, Goldman J et al (2006) Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108(6):1809–1820 91. Jabbour E, Kantarjian H, O'Brien S et al (2006) Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 107(2):480–482 92. O'Dwyer ME, Mauro MJ, Blasdel C et al (2004) Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 103(2):451–455 93. Deininger MW, Cortes J, Paquette R et al (2007) The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 110(7):1509–1519 94. Kovacsovics T, Maziarz RT (2006) Philadelphia chromosome positive acute lymphoblastic leukemia: impact of imatinib treatment on remission induction and allogeneic stem cell transplantation. Curr Onc Rep 8:343–351 95. Holowiecki J, Giebel S, Wojnar J et al (2008) Treosulfan and fludarabine lowtoxicity conditioning for allogeneic haemotopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 142(2):284–292 96. Mohty M, Szydlo RM, Yong AS et al (2008) Association between BMI-1 expression, acute graft-versus-host disease and outcome following allogeneic stem cell transplantation from HLA-identical siblings in chronic myeloid leukemia. Blood 112(5):2163–2166 97. Van der Meer A, Schaap NP, Schattenberg AV et al (2008) KIR2D55 is associated with leukemia free survival after HLA identical stem cell transplantation in chronic myeloid leukemia patients. Mol Immunol 45:3631–3638 98. Yong AS, Keyvanfar K, Eniafe R et al (2008) Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia-associated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy. Leukemia 22(9):1721–1727 99. Gordon MK, Sher D, Karrison T et al (2008) Successful autologous stem cell collection in patients with chronic myeloid leukemia in complete cytogenetic response, with quantitative measurement of BCR-ABL expression in blood, marrow, and apheresis products. Leuk Lymphoma 49(3):531–537 100. Olavarria E (2007) Autologous stem cell transplantation in chronic myeloid leukemia. Semin Hematol 44(4):252–258 101. CML Autograft Trials Collaboration (2007) Autologous stem cell transplantation in chronic myeloid leukemia: a meta-analysis of six randomized trials. Cancer Treat Rev 33(10):39–47 102. Gould SJ (1977) Ever since Darwin: Reflections in natural history. W.W. Norton & Company, New York 103. Gould SJ (1980) The Panda's thumb. W. W. Norton & Company, New York

Chapter 6 Allogeneic Transplantation for Hodgkin’s Lymphoma William Broderick and Patrick Stiff

1.  Introduction There are only approximately 7,500 cases of Hodgkin’s lymphoma diagnosed in the United States annually. While there is a bimodal distribution in incidence, the majority of cases occur in young adults 15–30 years of age [1]. Initial therapy is highly successful with progression-free survival (PFS) rates at 10 years of 70–90% for early stage disease and 60–70% for advanced disease. For those relapsing after initial therapy, 30–50% are long-term survivors after an autologous stem cell transplant, making this one of the most curable adult malignancies. However, a small minority of these typically young and otherwise healthy patients will relapse even after an autologous stem cell transplantation (ASCT) and it is for these rare patients that allogeneic transplantation has been increasingly considered. Initially discarded in the early 1990s as being too toxic utilizing myeloablative conditioning, allogeneic transplantation for this disease is increasing again based on the availability of reduced intensity regimens and therapies that have decreased mortality due to regimen-related toxicities, graft versus host disease (GVHD), and opportunistic infections. Whether or not this will be an effective approach for multiply resistant patients remains to be determined, making this one of the most controversial areas in 2008 in allogeneic transplantation. This chapter outlines modern therapy for this group of lymphomas and the potential utility of allogeneic transplantation in select patients.

2.  Conventional Therapy Initial therapy for patients with Hodgkin’s lymphoma is based primarily on stage, with early stage disease (stage I and II) without high risk features (B symptoms, bulky adenopathy, age >50 years) treated with radiation alone (stage I disease) or, short course chemotherapy combined with localized radiation therapy (stage II disease). Radiation alone in the past was usually reserved for patients with stage IA or IIA disease confirmed by laparotomy, however, From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_6, © Springer Science + Business Media, LLC 2003, 2010

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as PET scanning has recently replaced laparotomy as a staging tool, those with localized disease and a negative PET scan can receive mantle radiation with or without periaortic fields and expect a complete response (CR) >95%. Of these, approximately 70% of patients obtain a long-term remission and >90% of patients are alive 10 years from diagnosis [2]. To decrease relapses in early stage disease, the combination of abbreviated course chemotherapy with involved field radiation therapy (IFRT) is being increasingly used. Several studies have demonstrated that 2–4 cycles of ABVD chemotherapy followed by IFRT induces response rates >90% with 2–3 year follow up [2–4]. Patients presenting early stage disease with high risk features require systemic chemotherapy for optimal outcome. Patients with mediastinal masses >10 cm generally receive both full-course chemotherapy and IFRT. The addition of radiation to residual disease after chemotherapy, has also been shown to convert partial remissions (PR) in many to durable CRs with again a long-term survival of 70% [3, 4]. Patients with Stage III and IV disease require chemotherapy for optimal outcome. MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) was developed for use in Hodgkin’s disease in the 1960s and achieved high response rates and long-term survival rates of 50–60%. ABVD (doxorubicin, bleomycin, vinblastine DTIC) demonstrated activity, first in MOPP resistant patients, then as a first-line regimen with less gonadal toxicity and a lower risk of secondary malignancies than MOPP. It still remains the standard regimen for advanced Hodgkin’s disease in adults with CR rates reaching 70% (Table  6-1.) [5–7]. Failure-Free Survival rates (FFS) of 65%, and overall survival (OS) reaching 89% at 3 years. There is general agreement that IFRT even for responders is needed in the 25–30% of patients who are present with mediastinal masses >1/3 of the chest diameter. Studies have also shown that IFRT is effective in consolidating PRs as well [8].

Table 6-1.  Selected results of standard therapy for newly diagnosed Hodgkin’s disease. Stage

Treatment

Freedom from treatment failure

Long-term survival (%)

Early stage [4]

EFRT alone

67% (7 years)

92

ABVD + EFRT

88% (7 years)

94

ABVD

81% (5 years)

90

ABVD + IFRT

86% (5 years)

97

ABVD + EFRT

91.4% (10 years)

90.4

EBVM + EFRT

80% (10 years)

90.3

MOPP + EFRT

62.8% (7 years)

67.9

ABVD + EFRT

82.8% (7 years)

77.4

ABVD

63% (5 years)

82

MOPP/ABV

66% (5 years)

81

IA–IIIA [3] IA–IIIB [6] Advanced stage [5] IIIA, IIIB, IV [7]

Early stage: stage I or II disease, no bulky disease Advanced stage: stage III or IV disease, bulky stage II disease EFRT extended field radiation

Chapter 6  Allogeneic Transplantation for Hodgkin’s Lymphoma 

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3.  High-Dose Therapy with Autologous Stem Cell Transplantation For those who relapse after an initial chemotherapy-based treatment regimen, ASCT is generally the considered standard of care, particularly for those who relapse early. Patients who relapse >12 months after an initial CR, however, may be treated with combination chemotherapy and if they achieve a second CR, 30–50% will remain disease-free at 4 years without any further therapy [9, 10]. Most relapsing patients do so less than 12 months after a CR, and for these patients and those without a CR after initial therapy, standard dose second-line therapy is not likely to lead to a durable remission. In fact, longterm PFS is 0% for this group (Table 6-2.) [6]. For these patients, high-dose chemotherapy with ASCT has emerged as the treatment of choice. Overall 30–50% of such patients are alive and disease-free for 5+ years suggesting superiority of this approach for otherwise eligible patients. Several randomized trials have been performed to validate the efficacy of this approach. In 1993, the British National Lymphoma Investigation (BNLI) group published a 3-year event-free survival rate of 53% compared to 10% in their standard combination chemotherapy arm [11]. There was no difference in OS, but the follow up appeared not to have been long enough to demonstrate a survival benefit. The German Hodgkin’s Lymphoma Study Group (GHSG) in conjunction with the European Bone Marrow Transplant Registry (EBMTR) randomized heavily treated patients with relapse to chemotherapy or high-dose chemotherapy with ASCT [12]. They demonstrated a 55%

Table 6-2.  Results of autologous bone marrow transplant in Hodgkin’s disease. Importance of risk factors. Outcome by # of high risk features Study

n

Reece [13]

  58

High risk features

0

1

2

3+

(1) B-symptoms

3 years PFS 100%

3 years PFS 81%

3 years PFS 40%

3 years PFS 0%

43 months EFS 27%

43 months EFS 10%

3 years FFP 41%

3 years FFP <20%

(2) Extranodal relapse (3) CR <1 year Moskowitz [14]

  65

(1) B-symptoms

43 months EFS 83%

(2) Extranodal relapse (3) CR <1 year

Horning [15] 119

(1) Systemic symptomatic 3 years FFP relapse 85%

3 years FFP 51%

(2) Pulmonary or bone marrow relapse (3) More than minimal disease at BMT Stiff [16]

  81

(1) >2 prior regimens

5 years OS 60%

5 years OS 38%

(2) Relapse in radiation field (3) Extranodal relapse PFS progression-free survival, EFS event-free survival, FFP freedom from progression, OS overall survival

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freedom from treatment failure rate in the ASCT group compared to 34% in the chemotherapy group. Again, at a short follow up, no survival benefit was demonstrated.

4.  Risk Factors for Autotransplant Outcome Given the dismal results with standard salvage chemotherapy for those who relapse after initial combination chemotherapy and in lieu of performing randomized Phase III trials of ASCT therapy in North America, phase II trials were performed to determine which patients with relapsed disease would benefit most (Table 6-2). In 1994, Reece et al. transplanted 58 patients who had relapsed after an initial chemotherapy regimen [13]. All underwent highdose chemotherapy with ASCT and had a 3-year PFS rate of 64%, seemingly higher than what would be obtained with any available salvage chemotherapy. Three independent prognostic factors were identified: B-symptoms at relapse, extranodal disease at relapse, and initial remission duration of less than 1 year. Patients with 0, 1, 2, and all 3 risk factors had a PFS of 100, 81, 40, and 0%, respectively. Similar results have been presented by Mososkowitz et al. [14] and from the group at Stanford who identified pulmonary or bone marrow disease at relapse, systemic symptoms at relapse, and more than minimal disease as poor prognostic factors [15]. Freedom from progression 3 years after ASCT was estimated to be 85, 57, 41, and <20% for patients with 0, 1, 2, and 3 risk factors, respectively. The first US phase II cooperative group study for this patient group also identified three adverse risk factors for autotransplant outcome: >2 prior regimens, relapse in a radiated field, and extranodal disease [16]. Five-year OS was 60% for those with 0–1 risk factors versus 38% for those with 2 or 3 factors. Those transplanted in CR had a 70% long-term DFS. Thus, autotransplants appear to produce long-term survival in many patients with low and intermediate risk disease at the time of relapse (Table 6-2). Based on risk factor analysis, it should be a standard of care for these patients. For high-risk patients, however, only a minority are long-term survivors and new approaches are needed.

5.  Strategies to Improve Outcome in High Risk Disease To improve survival after an autograft particularly in patients with multiple adverse risk factors, several approaches have been investigated. First tried was multi-course, sequential HD chemotherapy with ASCT. In 1997, a multicenter phase II trial was undertaken treating relapsed or refractory patients with two cycles of standard-dose salvage chemotherapy, followed by sequential highdose chemotherapy with a final myeloablative course and an ASCT [17]. The toxicity was tolerable with no treatment-related deaths. FFS/OS rates were 64%/87% for patients with early relapse, 68%/81% for patients with late relapse, 30%/58% for patients with progressive disease (at enrollment), and 55%/88% for patients with multiply relapsed disease. The authors concluded that, given the high response rate in relapsed patients, this three-phase treatment regimen warranted further study. Another approach utilized a tandem autologous transplantation approach as proven successful in patients with multiple myeloma. This is based on the

Chapter 6  Allogeneic Transplantation for Hodgkin’s Lymphoma 

data suggesting that autograft outcome is optimal in patients transplanted in CR. In 1997, Ahmed et al. reported the results of tandem autologous transplant in 45 patients with refractory Hodgkin’s disease [18]. Their median survival was 45 months. However, only 55% of the patients were able to undergo the second transplant. Patients were excluded from the second cycle due to toxicity or progression. Brice et  al. treated 43 patients who failed induction therapy or who have poor prognosis defined as a <12 month interval between the end of treatment and first progression, stage III or IV disease at relapse, or relapse occurred in a previously irradiated site [19]. Also included were patients in first relapse who did not achieve a response during chemotherapy given at relapse. There were two treatment associated deaths, one with venoocclusive disease and one with acute respiratory distress syndrome. Overall, 39 patients underwent the first transplant and 32 underwent the second. Three patients progressed after the first transplant and did not proceed to the second transplant. Survival was better for patients receiving both transplants than for patients receiving one or no transplant (74% vs. 40% vs. 0%) [12]. Fung et al. conducted a two institution pilot study between 1998 and 2000 in which 41 primary refractory or recurrent Hodgkin’s lymphoma patients with at least 1 of 3 poor prognostic factors: first CR <12 months, extra nodal disease, or B-symptoms at relapse underwent tandem autologous transplant [20]. After a median follow-up time of 5.3 years, the reported OS, PFS, and FFS were 54, 49, and 55%, respectively. This approach is currently being further investigated in the Southwest Oncology Group (SWOG) together with the US BMT Clinical Trials Network (CTN). Despite advances in technique and improvement in survival over conventional salvage therapy ASCT has its drawbacks. Even the best outcome data predict a high rate of treatment failure in patients with poor risk factors at relapse. Also, exposure to high-dose chemotherapy can result in the development of myelodysplastic syndrome (MDS) or secondary acute myelogenous leukemia (AML), despite ASCT. Akpek et  al. reported in 2001 that 3 of their 104 Hodgkin’s disease autologous transplant patients developed secondary AML/MDS at 3, 7, and 12 years post-autograft [21]. Other reports confirm that the incidence of AML/MDS after ASCT for Hodgkin’s disease ranges from 5% to 25% [22, 23]. Despite these issues, current strategies are to improve ASCT outcome and continue to reserve allogeneic transplantation for those who fail an autograft.

6.  Allogeneic Transplantation for Hodgkin’s Lymphoma Patients who relapse after an ASCT have a median survival less than 1 year [24], with rare exceptions being those who relapse late, although a report of 11 highly selected patients reported by the EBMT who had a survival of 50% after a second ASCT procedure [25]. With the exception of these occasional patients, until recently, all patients relapsing after an ASCT died of their disease. It is this group that has been the subject of several novel approaches using allogeneic transplantation based on the hypothesis that like other lymphomas there is a GVL effect in this disease. The other advantages for an allograft in this disease are similar to that for other lymphomas including a lack of contamination of donor stem cells with malignant cells, the elimination of the risk of treatment-related AML and MDS after transplant, the ability

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to offer transplant therapy to those with an existing MDS, or those failing to mobilize sufficient stem cells for an ASCT. Evidence of a potential benefit of GVL in this disease was first reported in 1991 by Jones et  al. [26]. They reported that for transplants performed between 1981 and 1988, patients undergoing an allogeneic transplant had a 24% lower risk of relapse than those undergoing an autologous transplant. Given no significant difference in patient or treatment characteristics between ASCT and allogeneic transplant patients, this difference was postulated to have been due to GVL. This report is cited as the basis of nearly all future investigations of allogeneic transplantation in this disease.

7.  Early Results of Allografting in Hodgkin’s Disease Unfortunately, in their 1991 publication, Jones et al. also reported that 47% of allogeneic transplant recipients died of treatment-related causes, compared to 21% of ASCT recipients. Acute GVHD developed in 63% and chronic GVHD developed in 32% of the allograft patients who survived 100 days. The majority of deaths in this group resulted from GVHD. This difference in procedurerelated mortality resulted in the lack of a difference in event-free survival between those receiving ASCT and allografts [26]. With other studies reported over the next several years reporting high rates of lethal complications there was a general abandonment of allografting for this disease (Table 6-3). In 1993, Anderson et  al. reported the Seattle experience with allogeneic, syngeneic, and autologous BMT in patients with Hodgkin’s Disease [27]. In comparing all allogeneic transplant recipients to autologous and syngeneic recipients combined, the event-free survival rates (EFS) did not differ significantly, but there was a trend toward decreased relapse rate (48% vs. 77%, p = 0.060) but again a significant increase in nonrelapse mortality (58% vs. 41%, p = 0.047) in the allogeneic group. When the comparison was limited to HLA-matched sibling transplants versus ASCT, there was a nonsignificant difference in EFS rates (26% vs. 14%, p = 0.6) and nonrelapse mortality rates (53% vs. 43%, p = 0.2), but a significantly lower relapse rate among the HLAidentical transplants (45% vs. 76%, p = 0.50). In 1996, Milpied et  al. from

Table  6-3.  Results of allogeneic bone marrow transplantation in Hodgkin’s disease using fully ablative regimens. Study

Patients

Transplant

TRM (%)

OS

EFS/PFS

Anderson [27]

  68

Auto

32

13% (5 years)

14%, 5 years EFS

   6

Syngeneic

NR

33% (5 years)

NR

  53

Allo

53

20% (5 years)

22%, 5 years EFS

Gajewski [29]

100

HLA-matched sibling

61

21% (3 years)

15%, 3 years DFS

Milpied [28]

  45

Allo

48

25% (4 years)

15%, 4 years PFS

  45

Auto

27

37% (4 years)

24%, 4 years PFS

104   53

Auto Allo

26 43

37% (10 years) 30% (10 years)

26%, 10 years EFS for each cohort

Akpek [21]

DFS disease-free survival, EFS event-free survival, OS overall survival, PFS progression-free survival, TRM transplant-related mortality

Chapter 6  Allogeneic Transplantation for Hodgkin’s Lymphoma 

Centre Hospitalier Universitaire, Nantes, France, reported a review of 1,200 patients with Hodgkin’s Disease who underwent a transplant from various donors to the EBMTR [28]. Of these, 49 patients had undergone allogeneic transplant, 45 of whom had adequate information to complete a review were compared to 45 matched ASCT recipients. They reported no significant difference in response rate (84% vs. 83%) or 4-year relapse rate (61% vs. 61.5%) for the allograft and ASCT groups, respectively. There was, however, an increased rate of procedure-related mortality in the allograft group compared to the ASCT group (48% vs. 27%, respectively). The same year, Gajewski et  al. [29] published a review of 100 consecutive patients with Hodgkin’s disease who underwent HLA-identical sibling bone marrow transplants reported to the International Bone Marrow Transplant Registry (IBMTR). They reported a 3 year probability of relapse of 65% and a 3 year disease-free survival rate of only 15% [22]. All of the above authors pointed out that the recipients of allografts in their reviews had been more heavily pre-treated and many had suffered multiple relapses. The Seattle group pointed out that there was a higher risk of relapse in their patients with bulky disease. They did not note a statistical difference in survival or relapse among the various myeloablative preparatory regimens except for Gajewsiki et al. who did note a higher rate of treatment failure and relapse in patients who received busulfan and cyclophosphamide as their preparatory regimen. The lack of improvement in OS and a high TRM reported in these publications, in particular the IBMTR report and the debate over the limited effect if any of a GVL effect ,resulted in a period of time during which allogeneic transplant was severely limited. In particular, these results suggested that allografts after failed ASCT would be lethal in particular therapies.

8.  Reduced Intensity Regimens Given the evidence for GVL demonstrated in early studies and subsequent data indicating a response to donor lymphocyte infusions (DLI) in some [30], and the fact that the high mortality rate was frequently attributed to regimen-related toxicity, acute GVHD, and infections, several groups have continue to explore allografting in this disease while attempting to limit the transplant-related mortality by reducing the intensity of the preparatory regimens, using peripheral blood stem cells (PBSC) and/or depleting the T-Cell content of the grafts. In theory, the reduced intensity or nonmyeloablative preparatory regimens should result in less regimen-related deaths and the use of PBSC, in fewer infections. Of course, the drawback to a reduced intensity preparatory regimen is, less cytotoxic effect on the lymphoma itself. This places greater importance on the GVL effect and given the modest if any effect in the early studies this could permit progression of disease before the GVL effect begins after day 100. Depleting the T-cell content of the graft slows the advent of GVL and, consequently, the graft’s ability to control the lymphoma. Attempts to counter this delay have been early withdrawal of immunosuppression and DLI. These trials are shown in Table  6-4. In 2000, Anderlini et  al. at MD Anderson Cancer Center reported the results of a pilot study in which six patients with advanced HD who had failed a median of six chemotherapy regimens, radiation therapy, and auto-SCT underwent HLA-matched sibling allogeneic transplants [31]. The patients were considered eligible for allografting if

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Table  6-4.  Results of allogeneic bone marrow transplantation in Hodgkin’s disease using reduced intensity preparative regimens. Study

TRM Preparative Patients Transplant (%) regimen

OS

Outcome

Cooney [33]

  10

Allo

0

BEAM

90% (1 year)

70%, 1 year PFS

Robinson [38]

311

Allo

27

Various

46% (2 years)

26%, 2 years PFS

Peggs [35]

  49

Allo

16.3

Fludarabine, melphalan, alemtuzumab

56% (4 years)

39%, 4 years PFS

Anderlini [34]

  40

Allo

22

Fludarabine based

60% (18 months)

32%, 18 months PFS

Alvarez [34]

  40

Allo

25

Fludarabine, melphelan

48% (2 years)

32%, 2 years PFS

Baron [37]

  35

Allo

–

TBI ± fludarabine

35% (3 years)

8%, 3 years PFS

Alvarez [36]

  62

Auto ³ Allo

21

Fludarabine or low-dose TBI

62% (2 years)

36%, 2 years PFS

BEAM = BCNU, Etoposide, Cytosine Arabinoside, Melphelan, OS overall survival, PFS progression-free survival, TBI total body irradiation, TRM transplant related mortality

they had chemosensitive or stable disease after salvage chemotherapy. The conditioning regimens chosen were “less intensive” fludarabine-cyclophosphamide-antithymocyte globulin (ATG) (n = 4), fludarabine-melphalan (n = 1), and fludarabine-cytarabine-idarubicin (n = 1). Bone marrow recovery was prompt and at 30 days 4/5 evaluable patients had 100% donor chimerism. Two of the six died before day 100; neither of the deaths were conditioning regimen related. Beyond 100 days, one patient relapsed and died 8 months after transplant. The remaining three patients were alive and progression free after 9 months of follow up. As none of the above regimens would be expected to result in more than a transient response, the authors speculated that the durability of these remissions was secondary to a graft-versus-Hodgkin’s effect. They also concluded that, in the absence of progressive disease, allogeneic transplantation with reduced-intensity fludarabine-based conditioning is feasible in high risk, heavily pretreated Hodgkin’s disease patients with acceptable engraftment, and regimen-related toxicity. Following the success of BCNU, etoposide, Ara-C, melphalan (BEAM) as a conditioning regimen in autotransplant for HD, and a single case report of BEAM in allo-transplant in the British Journal of Haematology [32], Cooney et al. reported in 2003 on the use of this regimen from our group in ten patients with HD who also had failed prior autografts [33]. This more intensive regimen was chosen to insure an optimal cytoreduction of disease until day 100. Prior to transplant all patients received re-induction chemotherapy. At transplant one patient was in CR, four were in PR, three were in resistant relapse, and one had primary refractory disease. Patients received matched-sibling bone marrow (5), single-locus mismatched-sibling bone marrow (1), or matchedunrelated bone marrow (4). All patients engrafted rapidly and there were no deaths by day 100. All ten patients responded, eight complete responses and two partial responses. Twelve months after allograft, 9/10 patients were alive, seven in remission. Anderlini et al. followed up their initial results in 2005 with a report of 40 patients with relapsed or refractory HD [34] who underwent reduced-intensity

Chapter 6  Allogeneic Transplantation for Hodgkin’s Lymphoma 

allografts from either an HLA-matched sibling (20) or matched unrelated donor (20). The regimens chosen were fludarabine-cyclophosphamide +/− ATG and fludarabine-melphalan. Engraftment was rapid and day 100 and cumulative mortality were 5 and 22%, respectively. At a median of 13 months follow up, 24 patients were alive (60%); however, only 14 were in complete remission (23%). Eight patients died of treatment-related causes, and eight died of progressive disease. Of note, the fludarabine-melphalan regimen, which was considered the more intensive regimen, resulted in better OS (73% vs. 39%, p = 0.03) and a trend toward better PFS (37 vs. 21%, p = 0.2), further evidence that more intensive regimens are needed in this disease. Also in 2005, Peggs et al. published the collective experience in England including 49 patients with multiply relapsed Hodgkin’s disease [35]. Most (90%) of their patients had progressive disease after autologous transplant. They undertook allogeneic transplant with a fludarabine-melphalan-alemtuzumab regimen. Alemtuzumab was added to reduce the incidence of acute GVHD. They included both matched related (31) and unrelated (18) donor sources. All of their patients engrafted. Unlike the other groups reported above, 16 patients (33%) received DLI for residual disease or progression, 9 of whom responded to the DLI (eight complete, one partial). Nonrelapse-related mortality was 16.3% at 730 days. Projected 4-year overall survival and PFS were 55.7 and 39%, respectively. Additional experience with the fludarabine and melphalan regimen was presented in 2005 by Alverez et al. from Spain [36]. They treated 40 patients of whom 21 patients had received more than 2 chemotherapy regimens, 23 patients had received previous radiation therapy, and 29 patients had failed prior autologous transplant and 20 were transplanted in chemoresistant relapse. The response rate reported was 67% (21 complete remissions, 6 partial remissions). The 1 year transplant-related mortality was 25%. DLI was administered to 11 for relapse or refractory disease with 6 responses (3 complete and 3 partial). OS and PFS were 48 and 32%, respectively at 2 years. Refractoriness to chemotherapy was the only adverse prognostic factor noted. Extensive chronic GVHD was noted to be associated with a trend toward reduced relapse rate, but this did not reach statistical significance (77% vs. 44%, p = 0.07). As part of a larger study on autograft failures, the Seattle group reported on the use of fludarabine with 2 GY of TBI patients with Hodgkin’s lymphoma [37]. They found in 35 patients only an 8% 3-year PFS. Together these data suggest that regimen intensity may play a role in this disease. A registry review of the use of reduced intensity regimens as reported to the EBMT registry was published by Robinson et al. [38]. A total of 311 patients from 127 centers were reported. They had undergone a median of two lines of chemotherapy and 45% had undergone prior high-dose chemotherapy with autologous transplant. At transplantation, 158 patients had chemosensitive disease, 100 had chemoresistant disease, and 53 had untested relapse. Transplant donors were matched related donors (221), matched unrelated donors (61), and mismatched donors (16). PBSC were used in 263 of the cases. With a median follow up of 1 year, 59% of patients remained alive. The projected OS and PFS at 2 years were 46 and 26%. The 100 day transplant-related mortality was 17%, but transplant-related mortality increased to 24% at 1 year and 27% at 2 years. Chemoresistant disease again was also the only factor that predicted for worse for both PFS and OS (p < 0.0001).

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Evidence of a GVL effect is strongly suggested in these studies and comes from the following: a clinical response to DLI for those with relapsed or persistent disease [30], long-term survivors in patients treated with preparative regimens less aggressive than those used for their failed autograft, and a suggestion of a better outcome in patients with chronic GVHD. However, as relapses do occur after DLI the importance of GVL in this disease has not been fully clarified. Indeed, like chronic myeloid leukemia, it may be more effective as suggested in patients with chemosensitive, low tumor burden disease. With improvements in the management of GVHD and other regimen-related toxicities, and the suggestion in these studies that the more intensive reduced intensity regimens are associated with the best outcome, a reconsideration of fully ablative regimens seems warranted. While no such direct comparison has been reported, the EBMT reported a registry study that compared myeloablative and nonmyeloablative conditioning in Hodgkin’s disease [39]. The authors compared 97 patients undergoing allogeneic transplant after reduced intensity regimens to 93 patients transplanted after full myeloablative regimens. Nonrelapse mortality was significantly reduced in the reduced intensity group (HR 2.43, 95% CI 1.48–3.98, p £ 0.001). There was a trend toward improvement in progression free survival (HR 1.28, 95% CI 0.92–1.78, p = 0.1) and a statistically significant improvement in OS (HR 1.62, 95% CI 1.15–2.28, p = 0.005) as well for this group. As it appears that regimen intensity is becoming more defined for these patients, other strategies are being considered to decrease the high relapse rate associated with this therapy. Unpublished emerging data from our group suggest that disease burden at transplant is critical for long-term PFS, so combining disease burden reduction affected by an ASCT with the potential of a GVL effect from an allograft, a tandem approach seems appropriate to investigate. Such was recently reported by Carella et al. who treated ten patients with relapsed or refractory HD with a tandem approach of an ASCT with BEAM conditioning and then at a median of 84 days, these patients then underwent an allograft after a fludarabine/cyclophosphamide conditioning regimen [40]. In this high risk group, three patients achieved CR after the ASCT, but two of the three relapsed prior to allografting. One of them was able to attain CR with further chemotherapy. The remaining seven patients attained a PR after ASCT. Overall seven patients were alive at 210–700 days post-transplant, six in CR; two died of progressive disease and one died in CR of aspergillosis of the brain [31]. While these results are promising, larger studies with longer follow up will be necessary to confirm the results. However, with effective new agents emerging for the treatment of refractory Hodgkin’s lymphoma, simpler strategies may be as effective in maximizing responses prior to an allograft.

9.  Early Allogeneic Transplant in High Risk Patients While high-dose chemotherapy with ASCT has become the standard in patients who have failed multiple conventional chemotherapy and/or radiation regimens, a significant number of patients will fail ASCT as well and require further therapy, including allogeneic transplant. If this subset of patients could be identified prior to ASCT, they could be spared the morbidity of an ASCT and proceed directly to allografting. As detailed above, various studies of ASCT have identified patients not likely to do well. While tandem autografts

Chapter 6  Allogeneic Transplantation for Hodgkin’s Lymphoma 

may decrease the number who relapse, early allogeneic transplantation may be more advantageous in these high risk patients. In 2005, a prognostic model for prolonged event-free survival after autologous or allogeneic transplant was proposed by Hahn et al. [41]. They used a multivariate model to measure time to relapse, progression, or death. In their study, significant predictors of shorter event free survival were chemotherapy resistant disease, Karnofsky Performance Status <90, and three or more prior treatment regimens. Patients with two or three adverse factors had significantly shorter event-free survival (58% vs. 11%, p < 0.001) not only in autologous transplant but also in allogeneic transplants of 38% vs. 0%, p = 0.0022. In subsequent correspondence, it was suggested that this prognostic model may not be applicable to reduced intensity allogeneic transplants [42, 43]. As part of the US SWOG/CTN tandem ASCT study another multivariate analysis for outcome is to be done with future plans to select a group for an early allograft approach.

10.  Conclusions With standard chemotherapy and radiation, a CR is obtained in >90% of patients with early stage disease and >80% of advanced disease patients. Unfortunately, a significant minority of these young patients will not respond or will relapse. Options for these patients include salvage chemotherapy, autologous or allogeneic transplantation. ASCT has been shown to lead to a 30–70% long-term survival. Tandem ASCT have demonstrated success, but in some studies, a significant fraction of patients are not able to receive the second transplant. Multiple studies have now shown that there are significant adverse risk factors that predispose patients to failure of salvage chemotherapy and ASCT transplant. Analogous to the more common large cell lymphoma, there appear to be two distinct patient groups in Hodgkin’s disease. Late relapse with indolent, chemosensitive disease portends a good chance of cure with salvage chemotherapy or autologous transplant. Early relapse, chemoresistant disease, and progressive disease consistently have disappointing results with standard salvage regimens and ASCT. Early experience with allogeneic transplantation in high risk patients was also disappointing. While there was a notable decrease in relapses, there was also a high rate of transplant-related mortality. Consequently, despite some evidence of a GVL effect in Hodgkin’s lymphoma, allogeneic transplantation has typically been reserved for patients with biopsy-proven relapse after autografting, patients with chemoresistant disease, or patients in whom adequate stem cells could not be harvested for autologous transplant. Early studies of allogeneic transplants using reduced intensity conditioning regimens have demonstrated the ability to decrease transplant-related mortality, but more long-term follow up is necessary to demonstrate improvement in OS in Hodgkin’s Lymphoma patients (Table 6-4). Clearly, there is room for continued improvement in the treatment of high-risk Hodgkin’s lymphoma patients. Consideration is being given to moving allogeneic transplant with reduced intensity earlier in the algorithm for the treatment of high-risk patients. The theory is that the disease will not have been exposed to multiple chemotherapy regimens and may be more chemosensitive. Also, patients will have less change for a regimen-related lethal event and be physically more able to tolerate an allogeneic transplant. The use of maintenance therapy after transplant, as with histone deacetylase inhibitors being studied

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at our center, is also being investigated. The role of allogeneic transplant in Hodgkin’s disease continues to evolve. As more data with reduced intensity conditioning regimens become available and other innovative treatment adjuncts are tested, its role will become more defined.

References 1. Freedman AS, Nadler LM (1998) Malignancies of lymphoid cells. In: Fauci AS (ed) Harrison’s principles of internal medicine, 14th edn. McGraw-Hill, New York, p 708 2. Densmore JJ, Williams ME (2006) Lymphoproliferative diseases. In: Williams ME, Kahn MJ (eds) American society of hematology self-assessment program. Blackwell Publishing, Washington, DC, pp 260–264 3. Straus D, Portlock C, Qin J, Myers J (2004) Results of a prospective randomized clinical trial of doxorubicin, bleomycin, Vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) varsus ABVD alone for stages I, II, and IIIA non-bulky Hodgkin Disease. Blood 104:3483–3489 4. leMaignan C, Desablens B, Delwail V, Dib M, Berthou C (2004) Three cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or epirubicin, bleomycin, vinblastine, and methotrexate (EBVM) plus extended field radiation therapy in early and intermediate Hodgkin disease: 10-year results of a randomized trial. Blood 103:58–66 5. Engert A, Franklin J, Eich H, Brillant C, Sehlen S, Cartoni C (2007) Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: Final results of the GHSG HD7 trial. J Clin Oncol 25:3495–3502 6. Santoro A, Bonadonna G, Valagussa P, Zucali R, Vivani S, Villani F (1987) Longterm results of combined chemotherapy-radiotherapy approach in Hodgkin’s disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 5:27–37 7. Duggan D, Petroni G, Johnson J, Glick J, Fisher R, Connors J (2003) Randomized comparison of ABVD and MOPP/ABV Hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 21:607–614 8. Aisnberg AC (1999) Problems in Hodgkins disease management. Blood 93: 761–779 9. Josting A, Franklin J, May M, Koch P, Beykirch M, Heinz J (2002) New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the german Hodgkin’s lymphoma study group. J Clin Oncol 20:221–230 10. Bonfonte V, Santoro A, Vivani S, Devizzi L, Balzarotti M, Soncini F (1997) Outcome of patients with Hodgkin’s disease failing after primary MOPP-ABVD. J Clin Oncol 15:528–534 11. Linch DC, Winfield D, Goldstone AH et  al (1993) Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 341:1051–1054 12. Josting A, Raemakers J, Diehl V, Engert A (2002) New concepts for relapsed Hodgkin’s disease. Ann Oncol 13:117–121 13. Reece D, Connors J, Spinelli J, Barnett M (1994) Intensive therapy with cyclophosphamide, carmustane, etoposide +/– cisplatin and autologous bone marrow transplantation for Hodgkin’s disease in first relapse after combination chemotherapy. Blood 83:1193–1199 14. Moskowitz C, Nimer S, Zelenetz A, Trippett T (2001) A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin’s disease: Analysis by intent-to-treat and development of a prognostic model. Blood 97:616–623

Chapter 6  Allogeneic Transplantation for Hodgkin’s Lymphoma  15. Horning S, Chao N, Negrin R, Hoppe R (1997) High-dose therapy and autologous hematopoeitic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indicies. Blood 89:801–813 16. Stiff P, Unger J, Forman S, McCall A (2003) The value of augmented preparative regimens combined with an autologous bone marrow transplant for the management of relapsed or refractory Hodgkin disease: A southwest oncology group phase II trial. Biol Blood Marrow Transplant 9:529–539 17. Josting A, Rudolph C, Mapara M (2005) Cologne high dose sequential chemotherapy in relapsed and refractory Hodgkin’s and aggressive non-Hodgkin’s lymphoma – results of a multi-center phase-II study. Ann Oncol 16(1):116–123 18. Ahmed T, Lake D, Beer M (1997) Single and double auto-transplants for relapsing/ refractory Hodgkin’s disease: Results of two consecutive trials. Bone Marrow Transplant 19:449–454 19. Brice P, Divine M, Simon D, Coiffier B (1999) Feasability of tandem autologous stem-cell transplantation (ASCT) in induction failure or very unfavorable relapse from Hodgkin’s disease. Ann Oncol 10:1485–1488 20. Fung H, Stiff P, Schriber J, Toor A (2007) Tandem autologous stem cell transplantation for patients with primary refractory or poor risk recurrent Hodgkin lymphoma. Biol Blood Marrow Transplant 13:594–600 21. Akpek G, Ambinder RF, Piantadosi S, Abrams R (2001) Long-term results of blood and marrow transplantation for Hodgkin’s lymphoma. J Clin Oncol 19:4314–4321 22. Pedersen-Bjergaard J, Anderson M, Christiansen D (2000) Therapy-related acute myelogenous leukemia and myelodysplasia after high-dose chemotherapy and stem cell transplantation. Blood 95:3273–3279 23. Miller J, Arthur D, Litz C, Neglia J (1994) Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy. Blood 83:3780–3786 24. Vose JM, Bierman PJ, Anderson JR et  al (1992) Progressive disease after highdose therapy and autologous transplantation for lymphoid malignancy: clinical course and patient follow-up. Blood 80:2142–2148 25. VandenBerghe E, Pearce R, Taghipour G, Fouilard L, Goldstone AH (1997) Role of second transplant in the management of poor-prognosis lymphomas: a report from the European blood and bone marrow registry. J Clin Oncol 15:1595–1600 26. Jones RJ, Ambinder RF, Piantadosi S, Santos GW (1991) Evidence of a graftversus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 77:649 27. Anderson JE, Litzow MR, Appelbaum FR, Schoch G (1993) Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin’s disease: the 21-year seattle experience. J Clin Oncol 11:2342–2350 28. Milpied N, Fielding A, Pearce R, Ernst P (1996) Alogeneic bone marrow transplantation is not better than autologous transplantation for patients with relapsed Hodgkin’s disease. J Clin Oncol 14:1291–1296 29. Gajewski JL, Phillips GL, Sobocinski KA, Armitage JO, Gale RP (1996) Bone marrow transplants from HLA-identical siblings in advanced Hodgkin’s disease. J Clin Oncol 14:572–578 30. Anderlini P, Acholonu S, Okoroji G-J, Andersson B (2004) Donor leukocyte infusions in relapsed Hodgkin’s lymphoma following allogeneic stem cell transplantation: CD3+ cell dose, GVHD, and disease response. Bone Marrow Transplant 34:511–514 31. Anderlini P, Giralt S, Andersson B, Ueno N (2000) Allogeneic stem cell transplantation with fludarabine-based, less intensive conditioning regimens as adoptive immunotherapy in advanced Hodgkin’s disease. Bone Marrow Transplant 26:615–620

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W. Broderick and P. Stiff 32. Lush R, Jones S, Haynes A (2001) Advanced-stage, chemorefractory lymphocyte-predominant Hodgkin’s disease: Long-term follow-up of allografting and monoclonal antobody therapy. Br J Haem 114:734–735 33. Cooney J, Stiff P, Toor A, Parthasarathy M (2003) BEAM allogeneic transplantation for patients with Hodgkin’s disease who relapse after autologous transplantation is safe and effective. Biol Blood Marrow Transplant 9:177–182 34. Anderlini P, Saliba R, Acholonu S, Okoroji G-J, Donato M (2005) Reducedintensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin’s disease: low transplant-related mortality and impact of intensity of conditioning regimen. Bone Marrow Transplant 35:943–951 35. Peggs K, Hunter A, Chopra R, Parker A (2005) Clinical evidence of a graft-versusHodgkin’s-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet 365:1934–1941 36. Alvarez I, Sureda A, Caballero M, Urbano-Ispizua A (2005) Nonmyeloablative stem cell transplantation is an effective therapy for refaractory or relapsed Hodgkin lymphoma: results of a spanish prospective cooperative protocol. Biol Blood Marrow Transplant 12:172–183 37. Baron F, Storb R, Storer BE et al (2006) Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation. J Clin Oncol 25:4150–4157 38. Robinson S, Schmitz N, Taghipour G, Sureda A (2004) Reduced intensity allogeneic stem cell transplantation for hodgkin’s disease. Outcome depends primarily on disease status at the time of transplantation (abstract). Blood 104: Abstract 2322 39. Sureda A, Robinson S, Ruiz de Elvira C (2003) Non ablative allogeneic stem cell transplantation reduces transplant related mortality in comparison with conventional allogeneic transplantation in relapsed and refactory Hodgkin’s disease: results of the European group for blood and marrow transplantation. Blood 2003:692a 40. Carella A, Cavaliere M, Lerma E (2000) Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and NonHodgkin’s lymphoma. J Clin Oncol 18:3918–3924 41. Hahn T, Benekli M, Wong C, Moysich K (2005) A prognostic model for prolonged event-free survival after autologous or allogeneic blood or marrow transplantation for relapsed and refractory Hodgkin’s disease. Bone Marrow Transplant 25:557–566 42. Tey S, Butler J, Durrant S, Hill G, Morton J, Kennedy G (2005) Correspondence: a prognostic model for prolonged event-free survival after autologous or allogeneic blood or bone marrow transplantatin for relapsed and refractory Hodgkin’s disease. Bone Marrow Transplant 36:553–554 43. Hahn T, McCarthy P Jr (2005) Response to Tey et  al. Bone Marrow Transplant 36:554

Chapter 7 Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma J. Kuruvilla, P. Mollee, and J.H. Lipton

1.  Introduction The non-Hodgkin’s lymphomas (NHL) encompass a broad range of lymphoid malignancies that vary considerably in their underlying biology, natural history, and response to therapy. Classification schemas for NHL have evolved with the current World Health Organization (WHO) system attempting to identify biologically distinctive diseases that are usually associated with unique clinical presentation, natural history, and outcome. Conventional myeloablative allogeneic stem cell transplantation (allo-SCT) has long been studied in the treatment of acute leukemias and chronic myeloid leukemia. More recently allo-SCT has been increasingly applied to the management of NHL although the precise indications of allo-SCT in these disorders are not well defined. The role of allo-SCT in the treatment of NHL remains unclear. Randomized controlled trials have shown that autologous transplantation as part of secondline therapy appears to improve overall survival [1, 2], and several trials have evaluated autologous transplantation as consolidation compared to observation following primary chemotherapy for follicular lymphoma (FL) [3–5]. There are no randomized clinical trials of allo-SCT vs. autologous stem cell transplantation (ASCT) or conventional chemotherapy, nor do they seem likely. As the disease biology and thus the treatment approach (and particularly the availability of curative therapy) varies significantly between subtypes of NHL, few generalizations about allo-SCT can be made across all types of NHL. Determination of the optimal role and timing of allo-SCT in lymphoma requires an understanding of outcomes associated with allografting in each of the lymphoma subtypes as the outcome of the therapy can vary considerably between histologies as well as between different time points in the disease course. As such, the assessment of the role of allo-SCT in NHL is compromised by the paucity of quality trials in the literature. Most reports include highly heterogeneous patient cohorts with varying histologies (encompassing indolent and aggressive NHL as well as Hodgkin lymphoma), varying stages of disease (from patients in first complete remission to those in chemorefractory late relapse), and differing conditioning regimens (including reduced intensity From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_7, © Springer Science + Business Media, LLC 2003, 2010

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Table 7-1.  Conventional allogeneic stem cell transplantation for non-Hodgkin’s lymphoma. Advantages

Disadvantages

Normality of stem cells

Increased non-relapse mortality

Graft vs. lymphoma effect

Increased “allogeneic-related” morbidity

Avoidance of secondary AML/MDS

Age and donor restrictions

Absence of graft contamination by lymphoma

Increased costs

Alkylator and radiotherapy sensitive

Lack of randomized trials

regimens). There is a lack of central pathology review and most studies are affected by the many biases that come with retrospective cohort studies. Not surprisingly, the results of these studies are often inconsistent. 1.1.  Potential Advantages of Allo-SCT in NHL (Table 7-1) The lymphomas are generally sensitive, in a steep dose-response manner, to alkylating agents and radiation – agents that are typically employed in highdose conditioning regimens. Dose intensity (as demonstrated in the autologous setting) has been shown to improve response rates as well as potentially improving progression-free or overall survival [1, 2]. Evidence is accumulating (discussed below) that cure of lymphoma is not achieved purely via highdose therapy alone, but rather via the presence of a graft-vs-lymphoma effect (GVLy). There also appears to be a lower risk of secondary MDS/AML [6, 7] in comparison to ASCT [8]. The other advantage of using cells from an allogeneic donor is that they are not contaminated with lymphoma cells and the risk of infusing tumor cells is avoided. Similarly, a small population of patients who fail to obtain an autologous graft are obvious candidates for allo-SCT. 1.2.  Potential Disadvantages of Allo-SCT in NHL (Table 7-1) As seen with other transplant indications, any reduction in relapse achieved with allo-SCT is offset by mortality attributable to the treatment itself. The morbidity associated with allogeneic transplantation is also well recognized. Allo-SCT is limited by the availability of a suitably matched donor and has greater restrictions regarding recipient age, performance status, and organ function than ASCT. Finally, in comparison to ASCT, allo-SCT is an expensive way to deliver curative therapy to patients with malignant disease [9]. In this chapter, we summarize the evidence supporting myeloablative alloSCT in NHL on the basis of common individual disease histologies; follicular, mantle cell, diffuse large B cell (DLBC), and variants as well as lymphoblastic and Burkitt lymphoma.

2.  Allogeneic SCT in Indolent Lymphoma 2.1.  Introduction ASCT for FL has been evaluated in the front-line and relapsed setting and has resulted in an improved progression-free survival when compared to anthracycline-based chemotherapy [1, 3–5]. The randomized European CUP trial

Chapter 7  Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma 

was the only study to demonstrate an overall survival advantage for ASCT in a small group of patients with relapsed FL [1]. While ASCT has greater applicability in FL (compared to myeloablative allo-SCT) as it can be considered in patients up to age 65 or 70 years and may be performed with a relatively low treatment-related mortality (TRM), data fail to demonstrate a plateau in survival curves and there are concerns with secondary myelodysplasia and acute leukemia [1, 3–5]. Dose intensive chemotherapy has been demonstrated to improve progressionfree and overall survival in the relapsed lymphoma setting with the use of autografts to ameliorate the hematologic toxicity of high dose chemotherapy [1, 2]. Tumour graft contamination, as part of a SCT procedure, can be reduced through the use of purging strategies in the autologous setting (although the benefit of this remains a debatable point given the inconsistent published results) or eliminated through the use of syngeneic or allogeneic stem cells from a healthy donor [1, 10–13]. 2.2.  Is There a GVLy Effect in Indolent NHL? Donor-derived SCT offers the additional benefit of the GVLy effect that could provide sustained immune surveillance and a reduced rate of lymphoma recurrence in the recipient. The evidence of a GVLy effect has been indirectly suggested on the basis of a reduction in the rate of relapse in indolent NHL patients undergoing allogeneic SCT (allo-SCT) when compared to autologous SCT (ASCT), but the significance of this effect remains in question as this has never been tested in a large randomized trial [14–17]. Further direct evidence of a GVLy effect has been demonstrated through the use of donor lymphocyte infusion (DLI) that may induce remission in patients following allo-SCT [18–20]. 2.3.  Clinical Results in Indolent NHL Registry and single center reports have failed to clearly demonstrate the potential benefits of allo-SCT (particularly overall survival) and these data remain difficult to interpret because of sample size, patient selection, and study heterogeneity. Institutional studies are largely retrospective and include a mixture of indolent lymphoma subtypes although follicular lymphoma is the most indolent NHL subtype (Table  7-2). With a median follow-up of between 2 and 4 years, overall survival estimates range from 65 to 80% with non-relapse mortality of 20–35% [21–25]. The patients in these series are typically young (40–55 years of age) and may have a significant proportion of patients with refractory disease. Progression or event-free survival estimates range between 50 and 75% with few relapses reported. Larger series including registry series report comparative results of alloSCT with ASCT (Table 7-3). The smaller single institution series from MD Anderson and Utrecht are not matched with the allograft cohorts including more chemoresistant disease [26, 27]. However, the relapse rate appears higher in the ASCT arms of these retrospective series with a higher rate of non-relapse mortality in the allo-SCT cohorts although overall survival appears to favor the allograft patients. Patient selection remains a concern in

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Table 7-2. Single arm cohort studies detailing outcome of allo-SCT for ³20 patients with follicular lymphoma. N (all/ FL)

Refractory at alloSCT (%)

Toze (2000)

26/16

11/26

30% at 2 54% EFS years

58%

Median followup 2.4 years

Forrest [22]

24

1/22

21% at 2 78% PFS years

78%

Median followup of 2.3 years

33%

67%

Mandigers [23] 15/13 Kiss [24]

37/21

Yakoub-Agha [25]

16 (14 MA)

0

NRM

PFS/EFS

OS

Median Relapse follow-up

2/15

Median followup of 3 years

19%

70% RFS at 5 years

79% at 5 years

Median followup of survivors 4.2 years

5/16

55% EFS at 2 years

68% at 2 2 years

Median followup of 3.2 years

a Outcome includes all patients, not just those with intermediate-grade histology AlloSCT allogeneic stem cell transplantation, FL follicular lymphoma, NRM non-relapse mortality, PFS progression-free survival, EFS event-free survival, OS overall survival, MA myeloablative

the larger EBMT and IBMTR reviews but the registries have the advantage of larger patient numbers [10, 11]. The EBMT/IBMTR review included an analysis of patients with low grade NHL and compared outcomes of 199 allograft procedures (165 T-replete with 537 autografts; 394 unpurged and 143 purged) and 26 syngeneic transplants [10]. The relative risk of relapse was similar between syngeneic, T-cell replete and T-cell depleted allografts. Unpurged autografts had a statistically, significantly higher relative risk of relapse than syngeneic transplants suggesting that tumor cell contamination in autografting may be a larger factor in determining relapse than any putative GVLy effect present with an allograft. Overall survival was inferior in the T-cell replete allograft patients when compared to that in syngeneic recipients and this would be reflective of higher non-relapse mortality. A large study of patients with low grade NHL from the EBMT compared 231 allograft recipients with 2047 autograft patients [15]. The investigators also reported the results of a case control analysis (three matched ASCT patients for each allograft recipient) that was matched with status at SCT, year of SCT and age at diagnosis, SCT, and size of the largest lymphoma mass at SCT. A log-rank analysis demonstrated that overall survival and treatmentrelated mortality favored ASCT, progression-free survival was similar between allo-SCT and ASCT, and a reduced relapse rate was observed in the allo-SCT cohort. Overall, the data show that there appears to be a GVLy effect in indolent NHL as demonstrated by the demonstration of disease response with donor leukocyte infusion and series that show a reduced relapse rate in allograft recipients. Toxicity remains a significant concern and applicability remains an issue as myeloablative SCT is generally restricted to younger patients and TRM may be high (particularly when considering unrelated donor SCT).

10 18

Auto

14 697/2 047

Auto

Allo

1 185/231

Allo

68

Auto

597

Auto (Unpurged) 44

131

Auto (Purged)

Allo

176

26

143 (auto purged)

394 (auto unpurged)

34 (T-deplete)

165 (T-replete)

Allo

Syngeneic

Auto

Allo

0

3/10

NA

38% at 4 years

12%

34%

8%

14%

30%

NRM

22% at 2 years

68% at 2 years

NA

42.7% at 4 years

17% DFS

45% DFS

PFS/EFS

3/18

7/10

NA

51.1% at 4 years

34%

49%

55%

62%

51%

OS

83%

0

NA

NA

74%

19%

58%

43%

21%

Relapse

All chemosensitive

7/10 chemoresistant

Matched case control study showed better OS and NRM with ASCT, lower relapse with allo-SCT

Auto – 6% day 100 TRM, 6% TRM from t-MDS/AML

More chemoresistant in allo group

For OS, T-replete inferior to T-deplete and syngeneic SCT

Unpurged auto had higher RR for relapse than syngeneic

RR or relapse similar between allo and syngeneic, T-replete and T-deplete

Comment

Int-grade intermediate-grade non-hodgkin’s lymphoma, NRM non-relapse mortality, PFS progression-free survival, EFS event-free survival, OS overall survival, RR relapse rate

Verdonck

Peniket EBMT (2003)

Hosing MDACC (2003)

Van Besien IBMTR (2003)

Bierman IBMTR (2003)

N (all/FL)

Table 7-3.  Comparative analyses detailing outcome of transplantation for indolent histology non-Hodgkin’s lymphoma. Chapter 7  Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma  93

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2.4.  MUD BMT The role of matched unrelated donor (MUD) allo-SCT in indolent NHL has not been well studied. Institutional series report small numbers of MUD procedures but there are not many larger series. The largest series comes from the National Marrow Donor Program (NMDP) and reports the outcomes of 158 MUD recipients with NHL of whom 40 had indolent histology [28]. The 2-year PFS was 34% while actuarial mortality for the entire cohort at day 100 was 45%. The EBMT reported the outcomes of 56 MUD recipients with NHL of which six patients had indolent NHL [29], while the Japanese marrow donor program recently reported a series of MUD transplants including nine patients with FL [30]. Both series did not report specific outcomes for the indolent histology cases. 2.5.  When to Transplant? The optimal timing of allo-SCT in FL remains an open question; it is a disease with a typically indolent course that is frequently chemosensitive and patients may enjoy long remissions after therapies that may be intermittently applied over a number of years. While clinical factors such as those in the follicular lymphoma international prognostic index (FLIPI) may identify a high risk group of patients with a poor expected survival from diagnosis or at relapse, these prognostic factor analyses have not included therapy or remission duration as a factor [31]. Remission duration generally tends to shorten with the application of second-line or subsequent therapies, and therefore, multiple lines of therapy tend to be a significant factor in determining outcome as this is a marker of presumed chemoresistance. Allo-SCT is a therapy that will be used later in the disease course and given current clinical practice, patients will have received multiple applications of rituximab (with or without chemotherapy) and are likely judged to be “rituximab refractory” although this definition remains unclear. Results from carefully constructed prospective clinical trials that focus on discrete patients groups with a common histology will be required to allow allo-SCT to become one of the standard options that are available to patients with follicular lymphoma. Newer reduced intensity conditioning SCT (RICSCT) techniques are appealing as they increase the availability of allogeneic SCT procedures by increasing the upper age limit, expanding the limit of organ function and comorbidity and appear to reduce early TRM [20, 32–35]. RICSCT techniques improve the availability of allo-SCT to patients with FL in general; caution must be applied while interpreting results with short follow-up and consideration should be given to more proven strategies such as myeloablative allo-SCT in eligible patients.

3.  Allogeneic SCT in Mantle Cell Lymphoma Most patients with mantle cell lymphoma (MCL) present with advanced stage disease and while it is generally classified as an indolent lymphoma, its clinical behavior is usually one of an aggressive disease. Although conventional CHOP-like therapy, fludarabine-based therapy, and more recently, anti-CD20based therapies have shown increasing responses, the majority of patients will relapse and hence allo-SCT has been increasingly explored in this patient population.

Chapter 7  Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma 

3.1.  Is There a Graft-vs-Lymphoma Effect in MCL? Even though the literature in this area is limited, there is emerging evidence to support a GVLy effect in MCL. This includes reduced relapse rates after allografts, both in comparison to historic controls and to autografts [36–41]; disease response to withdrawal of immunosuppression [41]; delayed progressive post-transplant improvement in clinical or molecular remission status in the absence of anti-lymphoma therapy [36, 42, 43]; and clinical responses to DLI [19, 20, 36, 44–46]. In contrast, there is a substantial relapse rate postallo-SCT in an EBMT registry study [47] with similar relapse rates noted between auto- and allo-SCT in a report from the Johns Hopkins Cancer Center [48] and a lack of any plateau in the survival curves reported in an IBMTR registry study [38]. Thus while a GvLy effect clearly exists in MCL, questions remain regarding whether the GvLy effect is potent enough to overcome the almost inevitable risk of relapse in these patients. 3.2.  Clinical Results in MCL Several recent publications of myeloablative allo-SCT have expanded our understanding of allo-SCT in MCL (Table 7-4). The median age at transplant has been 45–50 years, several years less than the median age of patients with MCL, indicating the difficulty in broad application of conventional transplantation to this population. The small patient numbers and variety of conditioning regimens in these reports make interpretation of the data difficult. The largest experience comes from registry studies of the EBMT [49] and IBMTR [38], both having only been presented in abstract form. Vandenberghe [49] analyzed the outcomes of 22 patients with MCL and found a 2 year EFS and OS of 50 and 62%, respectively. The median follow-up was too short to establish any curative potential of allo-SCT. Armitage [38] presented the IBMTR experience of 212 patients (188 matched related donors and 28 unrelated or haploidentical donors). Sixteen percent of patients were transplanted in first remission, 38% in relapse or second remission and 46% were never in remission. With a median follow-up of 12 months (range, 3–106 months), EFS was extremely poor at 2 years with 2 year OS being ~40%. Disappointingly, there was no plateau in the EFS curve, even for patients transplanted in first remission. This registry data suggested that MCL remains incurable with conventional allo-SCT although follow-up is relatively short. Contrasting results are presented in the two small series with the longest follow-up. The City of Hope experience of 13 patients with a median follow-up of 4.75 years found a 3 year PFS of 53% with infrequent late relapses [39]. The Princess Margaret Hospital also detailed six patients with a median follow-up in excess of 4 years [37]. Remarkably, there was no TRM and no relapses in six patients, all with relapsed disease. One patient remains in remission 11 years post-transplant. Thus, for select patients, prolonged disease free survival and probable cure are achievable following allo-SCT. The importance of chemosensitivity in determining outcome after allo-SCT for MCL has been repeatedly demonstrated across most studies [36, 38, 49, 50]. This pattern is not dissimilar to that seen with ASCT, suggesting that there is only a limited role for allo-SCT to overcome chemoresistance. The importance of TBI in the conditioning regimen for mantle cell lymphoma remains uncertain. While an initial report in the autologous setting suggested that TBIbased conditioning was superior [51], this finding has not been supported by subsequent series [48, 52].

95

14 (+13 auto)

Laudi (2006)

48 years

47 years

29% at 5 years

50% at 5 years

19% at d100 44% at 5 years

Never in CR 46% Relapse/CR2 38% No refractory

28% refractory

N/A

N/A N/A

Relapse

Comment

49% at 5 years 21% at 5 years All patients chemosensitive No plateau in survival curve AlloSCT has increased NRM but lower relapse vs. autoSCT 49% at 5 years 1 Survival figures include 4 nonmyeloablative transplants

1 year FFP 90% vs. 44% for chemosensitive vs. refractory disease 42% at 3 years 37% at 3 years 20% at 3 years Refractory disease prognostic for worse EFS 1 late relapse at 51 months 100% at 100% at 0 1 patient in ongoing 4 years 4 years remission at 11 years 53% at 3 years 51% at 3 years 14% at 3 years 50% at 2 yr 62% at 2 yr N/A Refractory disease prognostic for EFS and OSa <20% at ~40% at N/A AlloSCT has increased 2 years 2 years NRM but lower relapse vs. autoSCT

OS

12% at 3 years 23% at 3 years N/A 55% at 3 years 55% at 3 years 1

CR1 16%

23% refractory N/A

0%

53% at 3 years

7 of 12 6 of 16

EFS/DFS

NRM non-relapse mortality, EFS event-free survival, DFS disease-free survival, OS overall survival, NA not available, FFP freedom from progression a  Both autologous stem cell transplant (autoSCT) and conventional allogeneic stem cell transplant (alloSCT)

17 (+80 auto)

Ganti [40]

212 (+553 auto) 50 years

47 years

No refractory

48.3 years

13 (+ 64 auto) 22 (+150 auto)

4% refractorya

55 yearsa

Berdeja [50] updated 19 (+ 38 auto) in Kasamon [48] and Kasamon (2007) Rifkind (2004) 6

Popplewell [39] Vandenberghe/ EBMT (2000) Armitage/IBMTR (2002)

25% refractory 5 refractory

47 years 52 years

12 (+ 16 auto) 16

Sohn (1998) Khouri [36]

a

a

Disease status at transplant NRM

N

Author

Median age

Table 7-4.  Selected studies (>5 patients) of conventional allogeneic stem cell transplantation in mantle cell lymphoma.

96  J. Kuruvilla et al.

Chapter 7  Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma 

Overall, conclusive evidence that conventional allo-SCT offers a cure for MCL is still lacking, although small numbers of patients with prolonged disease-free survival are appearing. The TRM associated with this procedure should preclude its use in first remission, but it may still play a role in patients in chemosensitive relapse.

4.  Allogeneic SCT in Aggressive Lymphomas 4.1.  Introduction Diffuse large B cell lymphoma (DLBCL) is the most common subtype of the aggressive or intermediate grade lymphomas; however, there are few reports of allo-SCT restricted to DLBCL. Most studies include a smattering of T-cell lymphomas and a variety of what is now considered to be indolent B cell lymphomas. Anthracycline-based chemotherapy with rituximab cures over 50% of patients with DLBCL [53], but for those with high-risk features at diagnosis or with relapsed disease, cure rates remain suboptimal. There is no randomized study demonstrating superiority of allo-SCT over other therapies as there is for ASCT [2], and as such, the use of allo-SCT in the management of aggressive histology lymphomas remains controversial and in many centers is somewhat unfashionable. 4.2.  Is there a Graft-vs-Lymphoma Effect in Aggressive NHL? Comparative trials of auto and allo-SCT have unfortunately revealed conflicting results regarding relapse rates with both positive [15, 54–56] and negative studies [57, 58]. Relapse is also neither consistently decreased in the presence of GVHD [15, 54, 55, 57, 59–62], nor increased after transplantation with T-cell depleted marrow [10, 63, 64]. Isolated but impressive cases of response to withdrawal of immunosuppression and to donor leukocyte infusions have also been reported in some [60, 65, 66], but not most cases [66, 67]. Biologically, differences in relapse between allo-SCT and ASCT may be due not only to GVLy, but potentially also to graft contamination by lymphoma cells or to greater efficacy of the TBI-based regimens generally used in alloSCT. To circumvent the issue of graft contamination in assessing relapse rates, Bierman recently reported a comparison of syngeneic transplants with auto and allo-SCT for lymphoma [10]. Compared to syngeneic transplants, there was no difference in relapse rates following allografts in the intermediate-grade lymphoma category. Thus, the evidence supporting a clinically meaningful graft-vs-tumor effect in intermediate-grade lymphoma is not compelling. It is possible that the slow acting GVLy effect is overridden by the rapidity of growth of the tumor. 4.3.  Clinical Results in Aggressive NHL Table 7-5 details select single arm cohort studies detailing specific outcomes of patients with aggressive non-Hodgkin’s lymphoma. While difficult to draw firm conclusions from these reports, they do demonstrate that long-term disease free survival is possible following allo-SCT even though transplantrelated mortality remains higher than that seen generally with autoSCT. Dhedin et  al [60] have published the largest detailed series of allo-SCT for

97

44/44

37/21

233/111

32/20

Doocey [68]

Juckett [64]

Kim [72]

Stein (2001)

44%

NA

29%

20%

37%

5 years PFS 40%

41% at 5 years

OS

5 years PFS 33%

NA 5 year EFS 11%a

N/A

42%a 17 of 32a

NA

NA

43% at 5 years

32% at 5 years

30% at 5 years

Relapse

Chemosensitivity most important prognostic factor

T cell depleted marrow. 5 years PFS 40% vs. 17% for chemosensitive vs. refractory disease

Durable remissions in chemorefractory patients

Subgroup of 22 patients with chemosensitive relapse had 60%PFS and 13% relapse

Comment

AlloSCT allogeneic stem cell transplantation, int-grade intermediate-grade non-Hodgkin’s lymphoma, NRM non-relapse mortality, PFS progression-free survival, EFS event-free survival, OS overall survival

15% at 5 year

35% at 5 years

N/A

25% at 1yr 5 years EFS 43% 48% at 5 years

32 of 73

PFS/EFS

 Outcome includes all patients, not just those with intermediate-grade histology

a

73/73

Dhedin [60]

Refractory at N (all/int-grade) alloSCT (%) NRM

Table 7-5.  Single arm cohort studies detailing outcome of alloSCT for ³20 patients with aggressive histology non-Hodgkin’s lymphoma.

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aggressive non-Hodgkin’s lymphoma (Burkitt’s and lymphoblastic lymphoma excluded). When the analysis was confined to 22 patients in chemosensitive relapse, the progression-free survival was 60%, a result that compares favorably with that in most ASCT series. The Vancouver group [68] noted a 5-year overall survival of 48% in 44 patients with intermediate-grade histology, some of whom were primary induction failures. The role of allo-SCT and ASCT for patients with aggressive NHL has been examined by a number of different comparative methodologies and is presented in Table 7-6. These reports, primarily from registry data, provide some guidance on the relative merits of the two approaches. A case-controlled study by the EBMT [57] matched 101 patients with lymphoma undergoing allo-SCT with 101 patients undergoing ASCT for disease status and stage at transplant, histological grade, transplant conditioning, age, sex, and time from diagnosis to transplant. Of these, 43 patients in each cohort had intermediate-grade lymphoma. Non-relapse mortality was less for ASCT patients (28% vs. 14%, p = 0.008), but there was no significant difference in PFS or relapse rates. The EBMT more recently compared allo-SCT and ASCT again using a matched case control design [15]. Of the 1185 patients undergoing allo-SCT 147 had intermediate-grade disease with resultant 42% non-relapse mortality, 35% PFS, and 38% overall survival at 4 years. In a matched (1:3) comparison with ASCT patients, relapse was reduced but overall survival was significantly worse as a result of the higher transplant-related mortality in the allo-SCT cohort. Bierman recently completed an analysis comparing syngeneic, auto-, and allo-SCT drawing patients from the EBMT, IBMTR, and ABMTR. [10] Five year disease-free survival was significantly worse for recipients of T-cell replete allogeneic grafts compared to those of syngeneic grafts (31% vs. 42%, p = 0.03), but there were no significant differences between syngeneic and autologous transplants. Similar findings were present with respect to overall survival. 4.4.  The Importance of Chemosensitivity The importance of chemosensitivity in determining outcome after allo-SCT for aggressive lymphoma has been repeatedly demonstrated across most studies and is the most consistent predictor of relapse, as well as event-free and overall survival [54, 55, 57–62, 64, 69–72]. 4.5.  MUD BMT With only 30%–40% of patients having a matched, related donor available, MUD transplants may increase the applicability of allo-SCT. Two registry reports describe outcomes for patients with aggressive histology lymphoma. The IBMTR [28] reported a series of 158 patients of whom 50 had intermediate-grade lymphoma. For the whole group, 100-day mortality was 45% and for the intermediate-grade group 2-year PFS was 35%. The EBMT has also reported their experience of 56 patients undergoing MUD BMT for lymphoma, 26 of whom were adults with aggressive non-Hodgkin’s lymphoma [29]. Transplant-related mortality was 42% and progression-free survival at 2 years was 16%. These reports indicate that while long-term survival is achievable for select patients, transplant-related mortality remains unacceptably high, limiting wider application of myeloablative MUD transplants.

99

Auto

49%

NA

35% at 4 years

42% at 5 years

34% at 5 years

31% at 5 years

PFS/EFS

24%

31% at 3 years

19% at 3 years

33% at 3 years

24% at 3 years

N/A

N/A

NA

38% at 4 years

48% at 5 years

39% at 5 years

32% at 5 years

OS

Comment

Matched case-control study of registry data

Matched case control study showed better OS and NRM with autoSCT, but increased relapse

Unusually high NRM in autoSCT

48% at 3 years Only diffuse large cell lymphoma

55% at 3 years Single centre retrospective study

35% (p = NS)

29%

NA

NA

29% at 5 years Syngeneic better OS and EFS than alloSCT, but not autoSCT

54% at 5 years

24% at 5 years No direct comparison of auto vs. alloSCT

Relapse

Int-grade intermediate-grade non-hodgkin’s lymphoma, NRM non-relapse mortality, PFS progression-free survival, EFS event-free survival, OS overall survival

51%

138/138

14%, Auto better 43% (p = NS) (p = 0.008)

28%

NA

45/45

101/43

14687/2863

Auto

Allo

1185/147

Allo

42% at 4 years

N/A

31/89

Syngeneic

N/A N/A

194/774

Auto (unpurged) 1417/2018

Allo (T-cell replete)

Aksentijevich Allo [71] Auto

Chopra [57]

Peniket [15]

Bierman [10]

N (all/int-grade) NRM

Table 7-6.  Comparative analyses detailing outcome of transplantation for aggressive histology non-Hodgkin’s lymphoma.

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4.6.  NK and T-cell Lymphomas There remains a paucity of published data in regard to the role of allo-SCT in the management of NK and T-cell lymphomas. A number of small series demonstrate that reasonable survivals are achievable, especially in chemosensitive disease, although non-relapse mortality remains high [60, 73–75]. Further research outlining outcomes in relation to the specific lymphoma subtypes is required. 4.7.  When to Transplant? As a general rule, allo-SCT should be reserved until conventional chemotherapy is highly likely to fail, but before the patient experiences the effects of advanced stage disease. With scant data regarding allografting intermediategrade lymphomas in first remission, allo-SCT should not be routinely offered to these patients. ASCT is currently the preferred therapy for patients with chemosensitive relapsed aggressive NHL, but allo-SCT may be appropriate, especially if ASCT is precluded because of inadequate stem cell collection or bone marrow involvement. While results for patients who have relapsed after ASCT are sobering, allo-SCT may also benefit highly select patients, particularly those in remission with excellent performance status, younger age, and non-aggressive relapse [76–79].

5.  Allogeneic Transplantation in Burkitt’s and Lymphoblastic Lymphoma 5.1.  Introduction Both Burkitt lymphoma (BL) and Lymphoblastic lymphoma (LBL) are uncommon NHL and together account for <5% of all cases. LBL differs from acute lymphoblastic lymphoma in the WHO classification as by definition it must have less than 25% bone marrow involvement with disease. BL and LBL are similar in that primary therapy emphasizes the use of intensive multi-agent chemotherapy incorporating high dose methotrexate, fractionated cyclophosphamide, steroids, and anthracyclines (similar to pediatric ALL regimens). The role of SCT is not clearly defined for either disease. Autologous transplantation has been utilized to consolidate first remission in a number of cases with a randomized trial in LBL published. Allo-SCT has been typically reserved for patients with high risk features as part of primary treatment or as part of a salvage strategy in more advanced disease. 5.2.  Clinical Results 5.2.1.  Burkitt Lymphoma The role of allo-SCT in BL has not been evaluated in a prospective study and results are typically included with the outcomes of transplantation for other lymphoma subtypes. Registry data of allo-SCT are only available in one large series from the EBMT [15]. Seventy-one patients underwent allogeneic transplant with 62 from matched sibling donors. Of this group, 25 patients underwent transplant in CR1. Median survival from the date of transplant was 4.7 months

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and actuarial survival at four years was 37.1%. TRM and PFS at 4 years were 31 and 34.9%, respectively. The EBMT also reported a matched analysis in a 3:1 autologous to allo-SCT ratio. Overall and progression-free survival along with TRM favoured auto-SCT for BL while the relapse rate was the same. Of note, the presence of acute GVHD did not appear to reduce the relapse rate raising the question of the impact of GVLy in this group of patients. Unfortunately, there are few published series of myeloablative allo-SCT that include more than 5 BL patients. 5.2.2. Lymphoblastic Lymphoma Allografting in LBL has also not been studied in a published prospective study. A randomized EBMT and United Kingdom trial demonstrated that an event-free survival improved but there was no overall survival benefit for autologous SCT over conventional chemotherapy in first remission [80]. There is an IBMTR/AMBTR review of 204 autologous and allogeneic transplants performed between 1989 and 1998. [81] Allo-SCT recipients (n = 76) had a higher incidence of TRM at six months (18% vs. 3%, p = 0.002) and the higher incidence was maintained at both one and five years post-SCT. The relapse rate post-SCT was statistically lower in allo-SCT recipients (34% vs. 56% at 5 years, p = 0.004. Although autologous SCT recipients had a higher survival at six months (75% vs. 59%, p = 0.01), survival appeared similar at one (60% vs. 49%, p = 0.09) and 5 years (44% vs. 39%, p = 0.47) post transplant. The transplant groups differed in that autologous SCT patients were older, more likely to receive PBSC and to have undergone transplant before 1994, and were less likely to have been transplanted with a TBI-containing regimen. The EBMT review of NHL also reported outcomes of 314 patients with LBL that underwent allo-SCT. Transplantation was under gone by113 patients in CR1 and 268 patients received transplants from a matched sibling donor. A-GVHD appeared to reduced the relapse rate in LBL (HR = 0.50, 95% CI = 0.39–91) suggesting the potential impact of a GVLy effect. Median OS post transplant was one year with an actuarial 4-year OS of 42%. PFS and TRM at 4 years were 37.7 and 33.2%, respectively. In a 3:1 matched analysis comparing autografted and allografted patients, OS, TRM, and PFS favored auto-SCT while the relapse rate post-SCT was improved in allo-SCT recipients. There are few non-registry series of greater than five patients undergoing allogeneic transplant for LBL in CR1 [80, 82, 83]. These studies include between 7 and 12 patients and report DFS of 59–91%. Similarly there is a paucity of allo-SCT series in CR2 or beyond [84, 85]. Reported disease-free survival was <20%. The role of allogeneic SCT remains unclear on the basis of these data. The published series vary in how they define high risk disease and will have the selection bias inherent to single institution and registry series. Further prospective series that will be collaborative in order to report sufficient patient numbers will be needed.

6.  Conclusions The role of myeloablative allogeneic stem cell transplantation in NHL lacks some clarity because of a lack of any randomized studies along with the limitations of registry data, and retrospective institutional series. However, the

Chapter 7  Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma 

principles of delivering dose intensity, providing an uncontaminated stem cell source, and the potential benefit of a graft-vs-lymphoma effect make allo-SCT an appealing option. Registry and institutional series demonstrate feasibility and encouraging results in indolent (follicular lymphoma) and aggressive (diffuse large B cell lymphoma and variants) subtypes. The data in highly aggressive lymphomas (Burkitt and lymphoblastic lymphomas) are less clear because of a paucity of data and clearly further study is required. Dose intensity remains an important concept in NHL (on the basis of randomized trial results utilizing autologous transplants) and thus caution must be applied when considering reduced-intensity transplants for patients in which a fully myeloablative allograft may be offered safely. Further studies are needed to clarify the role of myeloablative transplants in this era, where reduced intensity transplants are being embraced and targeted novel therapies are changing the landscape of lymphoma treatment.

References 1. Schouten HC, Qian W, Kvaloy S et al (2003) High-dose therapy improves progressionfree survival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918–3927 2. Philip T, Guglielmi C, Hagenbeek A et al (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapysensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540–1545 3. Lenz G, Dreyling M, Schiegnitz E et al (2004) Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: Results of a prospective, randomized trial of the German low-grade lymphoma study. Blood 104:2667–2674 4. Sebban C, Mounier N, Brousse N et al (2006) Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: The GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 108:2540–2544 5. Deconinck E, Foussard C, Milpied N et al (2005) High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: A randomized multicenter study by GOELAMS. Blood 105:3817–3823 6. Toze CL, Conneally EA, Connors JM et  al (2002) Allogeneic hematopoietic stem cell transplantation (AlloHSCT) for non-Hodgkin’s lymphoma (NHL) in Vancouver: 17-year experience of the Leukemia/BMT Program of British Columbia (BC) with related donor (RD) and unrelated (UD) donors. Ann Oncol 13:39a 7. Kiss TL, Abdolell M, Jamal N, Minden MD, Lipton JH, Messner HA (2002) Longterm medical outcomes and quality-of-life assessment of patients with chronic myeloid leukemia followed at least 10 years after allogeneic bone marrow transplantation. J Clin Oncol 20:2334–2343 8. Pedersen-Bjergaard J, Andersen MK, Christiansen DH (2000) Therapy-related acute myeloid leukemia and myelodysplasia after high- dose chemotherapy and autologous stem cell transplantation. Blood 95:3273–3279 9. Waters TM, Bennett CL, Pajeau TS et al (1998) Economic analyses of bone marrow and blood stem cell transplantation for leukemias and lymphoma: What do we know? Bone Marrow Transplant 21:641–650 10. Bierman PJ, Sweetenham JW, Loberiza FR Jr et al (2003) Syngeneic hematopoietic stem-cell transplantation for non-Hodgkin’s lymphoma: A comparison with allogeneic and autologous transplantation–the lymphoma working committee of the

103

104 

J. Kuruvilla et al. international bone marrow transplant registry and the European group for blood and marrow transplantation. J Clin Oncol 21:3744–3753 11. van Besien K, Loberiza FR Jr, Bajorunaite R et al (2003) Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102:3521–3529 12. Freedman AS, Neuberg D, Mauch P et al (1999) Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 94:3325–3333 13. Williams CD, Goldstone AH, Pearce RM et al (1996) Purging of bone marrow in autologous bone marrow transplantation for non-Hodgkin’s lymphoma: A casematched comparison with unpurged cases by the European blood and marrow transplant lymphoma registry. J Clin Oncol 14:2454–2464 14. Jones RJ, Ambinder RF, Piantadosi S, Santos GW (1991) Evidence of a graftversus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 77:649–653 15. Peniket AJ, Ruiz de Elvira MC, Taghipour G et  al (2003) An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: Allogeneic transplantation is associated with a lower relapse rate but a higher procedurerelated mortality rate than autologous transplantation. Bone Marrow Transplant 31:667–678 16. Schimmer AD, Jamal S, Messner H et  al (2000) Allogeneic or autologous bone marrow transplantation (BMT) for non-Hodgkin’s lymphoma (NHL): Results of a provincial strategy. Ontario BMT Network, Canada. Bone Marrow Transplant 26:859–864 17. Ratanatharathorn V, Uberti J, Karanes C et al (1994) Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with nonHodgkin’s lymphoma. Blood 84:1050–1055 18. Mandigers CM, Verdonck LF, Meijerink JP, Dekker AW, Schattenberg AV, Raemaekers JM (2003) Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation. Bone Marrow Transplant 32:1159–1163 19. Marks DI, Lush R, Cavenagh J et  al (2002) The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 100:3108–3114 20. Morris E, Thomson K, Craddock C et  al (2004) Outcomes after alemtuzumabcontaining reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood 104:3865–3871 21. Toze CL, Barnett MJ, Connors JM et al (2004) Long-term disease-free survival of patients with advanced follicular lymphoma after allogeneic bone marrow transplantation. Br J Haematol 127:311–321 22. Forrest DL, Thompson K, Nevill TJ, Couban S, Fernandez LA (2002) Allogeneic hematopoietic stem cell transplantation for progressive follicular lymphoma. Bone Marrow Transplant 29:973–978 23. Mandigers CM, Raemaekers JM, Schattenberg AV et  al (1998) Allogeneic bone marrow transplantation with T-cell-depleted marrow grafts for patients with poorrisk relapsed low-grade non-Hodgkin’s lymphoma. Br J Haematol 100:198–206 24. Kiss TL, Panzarella T, Messner HA et al (2003) Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and marrow transplantation in patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant 31:73–78 25. Yakoub-Agha I, Fawaz A, Folliot O et  al (2002) Allogeneic bone marrow transplantation in patients with follicular lymphoma: A single center study. Bone Marrow Transplant 30:229–234 26. Hosing C, Saliba RM, McLaughlin P et al (2003) Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin’s lymphoma. Ann Oncol 14:737–744

Chapter 7  Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma  27. Verdonck LF, Dekker AW, Lokhorst HM, Petersen EJ, Nieuwenhuis HK (1997) Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade non-Hodgkin’s lymphoma. Blood 90:4201–4205 28. Bierman P, Molina A, Nelson G, King R, Fay J, Champlin R (1999) Matched unrelated donor (MUD) allogeneic bone marrow transplantation for non-Hodgkin’s lymphoma: Results form the national marrow donor program (NMDP). Proc Am Soc Clin Oncol 18:3a 29. Singer CR, Taghipour G, Boogaerts MA et  al (1999) Matched unrelated donor (MUD) bone marrow transplantation for adults and children with non-Hodgkin’s lymphoma and Hodgkin’s lymphoma: Preliminary analysis of 56 cases reported to EBMT lymphoma registry. Blood 94:560a 30. Izutsu K, Kanda Y, Ohno H et al (2004) Unrelated bone marrow transplantation for non-Hodgkin lymphoma: A study from the Japan marrow donor program. Blood 103:1955–1960 31. Solal-Celigny P, Roy P, Colombat P et al (2004) Follicular lymphoma international prognostic index. Blood 104:1258–1265 32. Khouri IF, Keating M, Korbling M et al (1998) Transplant-lite: Induction of graftversus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817–2824 33. Khouri IF, Saliba RM, Giralt SA et al (2001) Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98:3595–3599 34. Kusumi E, Kami M, Kanda Y et al (2005) Reduced-intensity hematopoietic stemcell transplantation for malignant lymphoma: A retrospective survey of 112 adult patients in Japan. Bone Marrow Transplant 36:205–213 35. Van Besien K, Carreras J, Zhang M-J et al (2005) Reduced intensity vs myeloablative conditioning for HLA matched sibling transplantation in follicular lymphoma. ASH Annual Meeting Abstracts 106:656 36. Khouri IF, Lee MS, Romaguera J et  al (1999) Allogeneic hematopoietic transplantation for mantle-cell lymphoma: Molecular remissions and evidence of graftversus-malignancy. Ann Oncol 10:1293–1299 37. Rifkind J, Mollee P, Messner H, Lipton J (2005) Allogeneic stem cell transplantation for mantle cell lymphoma–does it deserve a better look? Leuk Lymphoma 46:217–223 38. Armitage JO (2002) Allotransplants for mantle cell lymphoma. Ann Oncol 13:9a 39. Popplewell LL, Nademanee A, Carter N et al (2004) Autologous vs allogeneic cell transplantation for mantle cell lymphoma (MCL): Outcomes over a 10-year period at city of hope. Blood 104:255a 40. Ganti AK, Bierman PJ, Lynch JC, Bociek RG, Vose JM, Armitage JO (2005) Hematopoietic stem cell transplantation in mantle cell lymphoma. Ann Oncol 16:618–624 41. Grigg A, Bardy P, Byron K, Seymour JF, Szer J (1999) Fludarabine-based nonmyeloablative chemotherapy followed by infusion of HLA-identical stem cells for relapsed leukaemia and lymphoma. Bone Marrow Transplant 23:107–110 42. Khouri IF, Lee MS, Saliba RM et al (2003) Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol 21:4407–4412 43. Maris MB, Sandmaier BM, Storer BE et al (2004) Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood 104:3535–3542 44. Sohn SK, Baek JH, Kim DH et al (2000) Successful allogeneic stem-cell transplantation with prophylactic stepwise G-CSF primed-DLIs for relapse after autologous transplantation in mantle cell lymphoma: A case report and literature review on the evidence of GVL effects in MCL. Am J Hematol 65:75–80

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J. Kuruvilla et al. 45. Escalon MP, Champlin RE, Saliba RM et al (2004) Nonmyeloablative allogeneic hematopoietic transplantation: A promising salvage therapy for patients with nonHodgkin’s lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol 22:2419–2423 46. Branson K, Chopra R, Kottaridis PD et al (2002) Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol 20:4022–4031 47. Robinson SP, Goldstone AH, Mackinnon S et al (2002) Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: An analysis from the lymphoma working party of the European group for blood and bone marrow transplant. Blood 100:4310–4316 48. Kasamon YL, Jones RJ, Diehl LF et  al (2005) Outcomes of autologous and allogeneic blood or marrow transplantation for mantle cell lymphoma. Biol Blood Marrow Transplant 11:39–46 49. Vandenberghe E, Ruiz de Elvira C, Isaacson P et  al (2000) Does transplantation improve outcome in mantle cell lymphoma (MCL)? A study from the EBMT. Blood 96:482a 50. Berdeja JG, Jones RJ, Zahurak ML et al (2001) Allogeneic bone marrow transplantation in patients with sensitive low-grade lymphoma or mantle cell lymphoma. Biol Blood Marrow Transplant 7:561–567 51. Milpied N, Gaillard F, Moreau P et  al (1998) High-dose therapy with stem cell transplantation for mantle cell lymphoma: Results and prognostic factors, a single center experience. Bone Marrow Transplant 22:645–650 52. Vandenberghe E, Ruiz de Elvira C, Loberiza FR et al (2003) Outcome of autologous transplantation for mantle cell lymphoma: A study by the European blood and bone marrow transplant and autologous blood and marrow transplant registries. Br J Haematol 120:793–800 53. Feugier P, Van Hoof A, Sebban C et  al (2005) Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d’Etude des lymphomes de l’Adulte. J Clin Oncol 23:4117–4126 54. Jones RJ, Ambinder RF, Piantadosi S, Santos GW (1991) Evidence of a graftversus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 77:649–653 55. Ratanatharathorn V, Uberti J, Karanes C et al (1994) Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with nonHodgkin’s lymphoma. Blood 84:1050–1055 56. Schimmer AD, Jamal S, Messner H et  al (2000) Allogeneic or autologous bone marrow transplantation (BMT) for non- Hodgkin’s lymphoma (NHL): Results of a provincial strategy. Ontario BMT Network, Canada. Bone Marrow Transplant 26:859–864 57. Chopra R, Goldstone AH, Pearce R et  al (1992) Autologous versus allogeneic bone marrow transplantation for non- Hodgkin’s lymphoma: A case-controlled analysis of the European bone marrow transplant group registry data. J Clin Oncol 10:1690–1695 58. Appelbaum FR, Sullivan KM, Buckner CD et  al (1987) Treatment of malignant lymphoma in 100 patients with chemotherapy, total body irradiation, and marrow transplantation. J Clin Oncol 5:1340–1347 59. Nachbaur D, Oberaigner W, Fritsch E, Nussbaumer W, Gastl G (2001) Allogeneic or autologous stem cell transplantation (SCT) for relapsed and refractory Hodgkin’s disease and non-Hodgkin’s lymphoma: A single- centre experience. Eur J Haematol 66:43–49 60. Dhedin N, Giraudier S, Gaulard P et al (1999) Allogeneic bone marrow transplantation in aggressive non-Hodgkin’s lymphoma (excluding Burkitt and lymphoblastic lymphoma): A series of 73 patients from the SFGM database. Societ Francaise de Greffe de Moelle. Br J Haematol 107:154–161

Chapter 7  Myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin’s Lymphoma  61. Mendoza E, Territo M, Schiller G, Lill M, Kunkel L, Wolin M (1995) Allogeneic bone marrow transplantation for Hodgkin’s and non-Hodgkin’s lymphoma. Bone Marrow Transplant 15:299–303 62. Mitterbauer M, Neumeister P, Kalhs P et al (2001) Long-term clinical and molecular remission after allogeneic stem cell transplantation (SCT) in patients with poor prognosis non-Hodgkin’s lymphoma. Leukemia 15:635–641 63. Soiffer RJ, Freedman AS, Neuberg D et  al (1998) CD6+ T cell-depleted allogeneic bone marrow transplantation for non- Hodgkin’s lymphoma. Bone Marrow Transplant 21:1177–1181 64. Juckett M, Rowlings P, Hessner M et  al (1998) T cell-depleted allogeneic bone marrow transplantation for high-risk non-Hodgkin’s lymphoma: Clinical and molecular follow-up. Bone Marrow Transplant 21:893–899 65. Bierman PJ (2000) Allogeneic bone marrow transplantation for lymphoma. Blood Rev 14:1–13 66. van Besien KW, de Lima M, Giralt SA et  al (1997) Management of lymphoma recurrence after allogeneic transplantation: The relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 19:977–982 67. Collins RH Jr, Shpilberg O, Drobyski WR et al (1997) Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 15:433–444 68. Doocey RT, Toze CL, Connors JM et al (2005) Allogeneic haematopoietic stemcell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma. Br J Haematol 131:223–230 69. Dann EJ, Daugherty CK, Larson RA (1997) Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin’s disease and non-Hodgkin’s lymphoma. Bone Marrow Transplant 20:369–374 70. Shepherd JD, Barnett MJ, Connors JM et al (1993) Allogeneic bone marrow transplantation for poor-prognosis non-Hodgkin’s lymphoma. Bone Marrow Transplant 12:591–596 71. Aksentijevich I, Jones RJ, Ambinder RF, Garrett-Mayer E, Flinn IW (2006) Clinical outcome following autologous and allogeneic blood and marrow transplantation for relapsed diffuse large-cell non-Hodgkin’s lymphoma. Biol Blood Marrow Transplant 12:965–972 72. Kim SW, Tanimoto TE, Hirabayashi N et  al (2006) Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: A nationwide survey in Japan. Blood 108:382–389 73. Rodriguez J, Munsell M, Yazji S et al (2001) Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 19:3766–3770 74. Feyler S, Prince HM, Pearce R et al (2007) The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: A BSBMT and ABMTRR study. Bone Marrow Transplant 40:443–450 75. Kahl C, Leithauser M, Wolff D et al (2002) Treatment of peripheral T-cell lymphomas (PTCL) with high-dose chemotherapy and autologous or allogeneic hematopoietic transplantation. Ann Hematol 81:646–650 76. de Lima M, van Besien KW, Giralt SA et al (1997) Bone marrow transplantation after failure of autologous transplant for non-Hodgkin’s lymphoma. Bone Marrow Transplant 19:121–127 77. Tsai T, Goodman S, Saez R et al (1997) Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation. Bone Marrow Transplant 20:859–863 78. Vandenberghe E, Pearce R, Taghipour G, Fouillard L, Goldstone AH (1997) Role of a second transplant in the management of poor-prognosis lymphomas: A report from the European blood and bone marrow registry. J Clin Oncol 15:1595–1600 79. Freytes CO, Loberiza FR, Rizzo JD et  al (2004) Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous

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J. Kuruvilla et al. stem cell transplantation for lymphoma: A report of the international bone marrow transplant registry. Blood 104:3797–3803 80. Sweetenham JW, Santini G, Qian W et  al (2001) High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: Results of a randomized trial of the European group for blood and marrow transplantation and the United Kingdom lymphoma group. J Clin Oncol 19:2927–2936 81. Levine JE, Harris RE, Loberiza FR Jr et  al (2003) A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 101:2476–2482 82. Bouabdallah R, Xerri L, Bardou VJ et al (1998) Role of induction chemotherapy and bone marrow transplantation in adult lymphoblastic lymphoma: A report on 62 patients from a single center. Ann Oncol 9:619–625 83. Milpied N, Ifrah N, Kuentz M et  al (1989) Bone marrow transplantation for adult poor prognosis lymphoblastic lymphoma in first complete remission. Br J Haematol 73:82–87 84. Morel P, Lepage E, Brice P et al (1992) Prognosis and treatment of lymphoblastic lymphoma in adults: A report on 80 patients. J Clin Oncol 10:1078–1085 85. van Besien KW, Mehra RC, Giralt SA et al (1996) Allogeneic bone marrow transplantation for poor-prognosis lymphoma: Response, toxicity and survival depend on disease histology. Am J Med 100:299–307

Chapter 8 Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning Sonali M. Smith and Ginna G. Laport

1.  Introduction Non-Hodgkin’s lymphoma (NHL) is the fifth most common cancer among men and women in the United States [1]. High-dose chemotherapy with autoHCT offers curative potential to some patients who are not cured with frontline combination chemotherapy and/or radiotherapy. However, autoHCT is not the optimal therapy for patients with marrow involvement or for some patients with indolent disease. Conventional myeloablative allogeneic hematopoietic cell transplantation (HCT) has unequivocally demonstrated a reduction in relapse/progression compared with autoHCT in both indolent and aggressive NHL but is also associated with significant treatment-related mortality (TRM) [2, 3]. Over the last decade, the use of nonmyeloablative or reduced intensity conditioning (RIT) regimens has increased with an associated reduction in upfront toxicity in most published studies. RIT regimens broaden patient eligibility since older patients, patients with comorbid conditions, and heavily pretreated patients, including those who have failed a prior autoHCT can better tolerate such regimens. This approach incorporates immunosuppressive doses of chemotherapy and/or radiotherapy to achieve a mixed donor-host hematopoietic chimeric state, thus facilitating development of a donor immune-mediated graft-versus-lymphoma (GVL) effect. Limitations of RIT regimens include the relatively slow disease response as several weeks to a few months is required for a maximal GVL effect. Thus, the delayed immune responses will not occur rapidly enough in patients with a large tumor burden or rapidly proliferating disease. Another limitation of RIT is the variable susceptibility among hematologic malignancies to the GVL effect. Not surprisingly, the indolent NHL subtypes are most sensitive to the adoptive immunotherapy effect since these diseases demonstrate slower proliferation rates allowing time for the GVL effect to establish. In contrast, high-grade lymphomas appear to be the least sensitive to reduced intensity regimens. This chapter covers the most recent results involving the use of allogeneic RIT regimens for patients with indolent and aggressive NHL. Most of the larger studies published to date are retrospective in nature while smaller studies From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_8, © Springer Science + Business Media, LLC 2003, 2010

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originate from single institutions. Numerous conditioning regimens of varying dose intensities are being utilized, making it difficult to draw definitive comparisons across the various trials. The published data so far show high engraftment rates and sustained remissions, but graft versus host disease (GVHD) and infection remain the leading causes of TRM.

2.  Follicular Non-Hodgkin’s Lymphoma Follicular non-Hodgkin’s lymphoma (FL) is the second most frequent subtype of NHL with approximately 15,000 cases per year diagnosed in the United States. Median survival has historically ranged from 7 to 10 years, but newer agents such as monoclonal antibodies and radio immunoconjugates have improved response rates and early results show that overall survival (OS) may actually be affected [4, 5]. The definitive management of patients with advanced follicular NHL remains under considerable debate due to the numerous treatment options available. HCT has been offered to FL patients as an alternative approach, especially to younger patients, but typically was offered late in their course because of the long natural history inherent in this disease and the TRM associated with HCT. Refinements in HCT and improved supportive care have lowered TRM and thus may alter this paradigm. It is worth noting that most published transplant trials were initiated in the prerituximab era, which limits our current knowledge regarding the influence of rituximab on the outcomes of patients undergoing HCT [6, 7]. The addition of rituximab to frontline chemotherapy has improved the progression-free survival and OS for newly diagnosed FL patients and only longer follow-up will reveal the true impact of upfront chemoimmunotherapy [8, 9]. AlloHCT represents the only treatment modality with curative potential for patients with advanced FL. Although no randomized trials have been performed, several studies have consistently reported a lower risk of relapse compared to autoHCT. But the TRM associated with myeloablative alloHCT has invariably offset the benefit conferred by lower relapse rates. A Center for International Bone Marrow Transplant Research (CIBMTR) report compared the outcomes of 904 patients with FL who underwent either myeloablative alloHCT (n = 176), purged autoHCT (n = 131), or unpurged autoHCT (n = 597). The risk for relapse was 54% lower in the allogeneic recipients (p < 0.001) and 26% lower in recipients of purged autografts (p = 0.04) than in recipients of unpurged autografts [3]. However, the risk of TRM was 4.4 times higher after alloHCT than after autoHCT (p < 0.001), resulting in comparable 5-year probabilities of OS (52% after allogeneic, 62% after purged autologous, and 55% after unpurged autologous).

3.  Allogeneic Reduced Intensity Conditioning FL is a malignant disease that may be the most amenable to reduced intensity conditioning since (1) its indolent disease course allows establishment of the GVL effect and (2) the older median age of FL patients typically precludes them from receiving a myeloablative regimen. With follow-up ranging from 1 to 3 years, several studies utilizing various RIT regimens using matched related (MRD) and unrelated donors (URD) have reported disease-free survival (DFS) and OS ranging from 65% to 84% and 73% to 85%, respectively, with TRM reported from 10% to 18%. Table 8-1 lists

73

47

French registry [10] 2007

M.D. Anderson [12]

45

41

28

Japanese multicenter [65] 2005

UK multicenter [15] 2004

UK multicenter [14] 2004

46 (18–60)

48 (18–73)

48 (61–32)

54 (34–67)

53 yo

51 yo (33–66)

Median age (range)

Alemtuzumab BEAM

Alemtuzumab, flu Melphalan

Flu-based or low Dose TBI

Flu ± TBI

Flu, rituximab, cyclophosphamide

Flu-based

MRD URD

MRD URD

MRD URD

MRD URD

MRD URD

MRD URD

Stem Cell Preparative regimen source

69

65

83 sens 64 res

51

85

51

74

73

79

58

88

56

1.4

3

3

2

3

3

44 10

17a

 2

15

 8

10

13

11

18

34

19

32

TRM Relapse (%) (%)

15

49

60

11

34

Follow up Acute DFS/PFS (%) OS (%) (yrs) GVHD (%)

FHCRC Fred Hutchinson Cancer Research Center, flu fludarabine, PFS/EFS progression free survival/event free survival, OS overall survival, yrs years, UK United Kingdom, TBI total body irradiation, MRD matched related donor, URD, unrelated donor, BEAM carmustine, etoposide, cytarabine, melphalan, TRM treatment-related mortality, sens chemosensitive disease, res chemoresistant a  Grade 1–2 GVH only b  Includes all histologies

45

FHCRC [64] 2005

2005

n

Group/year

Table 8-1.  Allogeneic nonmyeloablative/reduced intensity transplantation for follicular NHL.

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these trials. Patient ages ranged from 18 to 73 years, and all studies included patients who had failed prior autoHCT and/or who had been heavily pretreated. The report with the largest number of patients comes from the French Registry, Societe Francaise de Greffe de Moelle Osseuse et de Therapie Cellulaire [10]. Seventy-three patients with indolent lymphoma received a fludarabine-based RIT regimen and received an allograft either from an MRD or from URD. Predictably, chemosensitivity significantly influenced event-free survival (EFS), OS, and TRM. The 3-year OS rates for patients in complete remission (CR), partial remission (PR) or with chemoresistant disease at the time of alloHCT were 66, 64, and 32%, respectively (p = 0.001). TRM rates were 32, 28, and 63%, respectively (p = 0.005). Relapse incidence was 10% for all patients with a median follow-up of 37 months. The most promising data are from the M.D. Anderson Cancer Center. Twenty patients with relapsed indolent NHL (including 18 follicular patients) who had matched sibling donors received RIT with fludarabine and cyclophosphamide ± high-dose rituximab [11]. Twelve patients were in second or greater CR at the time of transplantation. The CR rate was 100% after transplantation. DFS and OS at 2 years were both ~84%. The incidence of grade II–IV acute GVHD and chronic GVHD was 20 and 64%, respectively. Only one patient died from a treatment-related complication. These results were recently updated with a total accrual of 47 patients. With a median follow-up of 34 months, the 3-year DFS, OS, and risk of progression were 88, 85, and 3%, respectively [12]. This FCR regimen was notable for the use of high dose of rituximab at 1 g/m2 for three doses with a dual intent of upfront disease control and as part of GVHD prophylaxis [13]. These encouraging data support the existence of a GVL effect, although longer follow-up is necessary to confirm a true plateau in survival and confirmation in a multicenter setting is currently ongoing in the United States. Because GVHD remains a leading cause of TRM in the RIT setting, some investigators have incorporated alemtuzumab (anti CD-52 humanized monoclonal antibody) in the preparative regimen for in vivo donor T cell depletion. Graft rejection is also reduced since recipient T cells are also affected. Two separate groups from the United Kingdom have reported remarkably low acute GVHD rates with grade 3–4 acute GVHD being completely eliminated in the report by Faulkner et al. [14]. In this report, 65 patients including 28 patients with low-grade NHL received a BEAM-alemtuzumab conditioning regimen. Estimated 1-year TRM was only 8% with relapse/progression being the major cause of treatment failure. Relapse did not occur in any patient who developed acute or chronic GVHD although this association did not reach statistical significance. The other series from the United Kingdom that also utilized an alemtuzumab-containing regimen reported a 15% incidence of grade 2–4 acute GVHD [15]. However, this report demonstrated the highest rate of relapse compared to other comparable series suggesting that the in vivo T cell depletion induced by alemtuzumab may compromise the GVL effect. Further details regarding the use of alemtuzumab are further discussed in the Novel/ Emerging Therapies section of this chapter. A recent analysis from the CIBMTR confirmed the increasing utilization of RIT regimens for FL patients [16]. In 1997, <10% of matched sibling allogeneic transplants reported to the registry employed RIT regimens with this percentage increasing to 80% by 2002. The outcomes of 120 myeloablative recipients were compared to 85 RIT recipients. Interestingly, PFS, OS, and

Chapter 8  Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning 

TRM did not differ between the two groups. The 3-year PFS and OS were 65 and 55%, and 70 and 64%, respectively. However, relapse/progression was higher in the RIT group, 21 versus 9% (p = 0.03). It should be noted that nearly one-third of patients had chemotherapy-resistant disease and that the RIT recipients had an older median age (50 vs. 45 years) and a longer time from diagnosis to transplantation (34 vs. 24 months). Chemosensitivity and recipient performance status were better predictors of outcome than the conditioning regimen utilized. For patients with FL, RIT regimens have shown promising results and have broadened patient eligibility. However, patients with chemoresistant disease or who have received multiple prior regimens are not likely to benefit from this modality. The advent of prognostic indices such as the Follicular Lymphoma International Prognostic Index (FLIPI) and gene-expression profiling may allow earlier identification of patients who could benefit from alloHCT sooner rather than later [17, 18].

4.  Mantle Cell Lymphoma Mantle cell lymphoma (MCL) accounts for 5–10% of all lymphoma cases and is characterized by the t(11;14) translocation resulting in rearrangement of the bcl-1 locus and cyclin D1 protein overexpression. The median age at diagnosis is about 60-years old and, despite high initial response rates with conventional chemotherapy, the median PFS and OS are only 1 and 3 years, respectively [19]. AutoHCT in first remission has been shown to prolong EFS and possibly OS, but a definitive plateau in survival has not been demonstrated so far [9, 20, 21]. Myeloablative alloHCT can induce durable remissions in MCL patients with refractory or relapsed disease but is associated with high upfront mortality. As with FL patients, the median age of patients with MCL is ~60-year old, which deems such patients suboptimal candidates for myeloablative regimens. As seen with most other NHL subtypes, the existence of a GVL effect in MCL stems from findings of lower relapse rates after alloHCT compared to autologous HCT. Further support for GVL in MCL includes the delayed conversion of polymerase chain reaction (PCR) positivity to PCR negativity in bone marrow and the observation of disease regression following either withdrawal of immunosuppression or appearance of chronic GVHD [22, 23] (Table 8-2). The European Bone Marrow Transplant Group (EBMT) has reported the largest experience to date with 144 MCL patients who received various RIT regimens [24]. Many patients were heavily pretreated, and 42% had failed a prior autograft. One hundred patients had chemosensitive disease with the rest of the patients being either chemorefractory or untested. The 2-year relapse rate, PFS, and OS were 57, 26, and 31%, respectively. However, the TRM was a prohibitive 50% at 2 years. Patients with chemoresistant disease had a significantly lower PFS and higher TRM compared to patients with chemosensitive disease. In a recent separate study, the results of 66 MCL patients who were URD recipients were analyzed by the EBMT [25]. Forty-four patients (67%) received an RIT regimen. After a median follow-up of 15 months, the 2-year PFS and OS were 28 and 42%, respectively, for all patients. The RIT recipients did not have a lower nonrelapse mortality (NRM) or improved survival compared to the myeloablative patients but the RIT group was older and heavily pretreated.

113

  66

144

  33

  18

  10

EBMT [25] 2006

EBMT [66] 2005

FHCRC [26] 2004

M.D. Anderson [67] 2005

UK multicenter(15) 2004

FCR or Flu/cisp/araC Alemtuzumab, flu Melphalan

48b (18–73)

Flu + TBI

Various

33% ablative 67% RIT

57 (46–64)

54 (33–70)

49 yo (28–68)

50 yo (22–68)

MRD URD

MRD URD

MRD URD

MRD URD

URD

50

82

60

26

28

60

85

65

31

42

  3 years

26 months

  2 years

  9 months

15 months

Median age Stem cell DFS/PFS Follow up (range) Preparative regimen source (%) OS (%) (yrs)

15

17

57

36

35

52

17

 9

57

45

Acute GVHD Relapse (%) (%)

11b

  0a

  24

  50

  27

TRM (%)

FHCRC Fred Hutchinson Cancer Research Center, flu fludarabine, PFS/EFS progression free survival/event free survival, OS overall survival, yrs years, UK United Kingdom, TBI total body irradiation, MRD matched related donor, URD unrelated donor, BEAM carmustine, etoposide, cytarabine, melphalan, TRM treatment-related mortality, sens chemosensitive disease, res chemoresistant a  Day + 100 TRM b  Data for all 88 NHL patients

n

Group/year

Table 8-2.  Allogeneic nonmyeloablative/reduced intensity transplantation for mantle cell NHL.

114  S.M. Smith and G.G. Laport

Chapter 8  Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning 

Investigators from the Fred Hutchinson Cancer Research Center (FHCRC) utilized a fludarabine and low-dose total body irradiation (TBI) regimen with 33 MCL patients [26]. This group of patients was heavily pretreated as the median number of prior regimens was 4 and 14 patients had received a prior autoHCT. With a median follow-up of 24 months, the 2-year DFS and OS were 60 and 65%, respectively, with a 24% NRM. These results are particularly notable considering that 85% had failed front-line or salvage therapy and 36% had chemoresistant disease. The only pretransplantation factor predictive of relapse was number of prior regimens and, in contrast to the EBMT report, chemorefractory disease did not appear to affect relapse rate. The M.D. Anderson group described the outcomes of 18 MCL patients with chemosensitive disease who received predominantly the FCR regimen (fludarabine, cyclophosphamide, rituximab) [27]. The median age was 57-year old and most patients (89%) had chemosensitive disease with five patients who had failed a prior autoHCT. The 3-year EFS and OS were an impressive 82 and 85%, respectively with a 0% mortality at day + 100. Compared to the abovementioned FHCRC study and the EBMT series, the higher EFS and OS in this study may be explained by the better risk patient group since the majority patients were chemosensitive at the time of transplantation. A study from the United Kingdom with 188 NHL patients included 10 patients with MCL [15]. The 3-year PFS and OS were 50 and 60%, respectively with an actuarial relapse rate of 50% for the 10 MCL patients. The RIT regimens were alemtuzumab-based which was more immunosuppressive compared to other RIT regimens and may thus impair the GVL effect. In summary, the above data support the existence of graft versus lymphoma effects in patients with MCL. The use of allogeneic RIC is increasing and early results appear promising even for patients with MCL who have failed a prior autoHCT. However, longer follow-up is necessary to confirm a true plateau in survival.

5.  Aggressive B-cell Lymphomas Diffuse large B-cell lymphoma (DLCL) and other aggressive NHL subtypes are generally chemosensitive diseases with high initial response rates to combination chemotherapy. Nevertheless, almost half of patients with aggressive NHL eventually relapse and become candidates for further therapies. AutoHCT is the standard of care for relapsed chemosensitive aggressive lymphomas, but not all patients demonstrate chemosensitivity, and recurrence after autologous transplantation remains problematic [28, 29]. Myeloablative alloHCT transplants have demonstrated efficacy against relapsed DLCL but TRM rates of 25–41% dampen enthusiasm for this approach and less intensive regimens are of interest [30–33]. Currently, the role of reduced intensity allogeneic transplant remains least well-defined for aggressive NHL, and there is a paucity of studies focusing solely on this patient population. One concern is the lack of sufficient disease ablation with less intensive regimens. As an example, a retrospective comparison of 16 patients with aggressive NHL undergoing conventional myeloablative transplant to 12 patients undergoing reduced intensity regimens showed a higher 2-year relapse rate with less intensive conditioning (44 vs.

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12%, p = 0.02) [2]. In addition, most reports show a higher NRM and lower disease control for aggressive NHL as compared to indolent subtypes [14, 15, 24]. The EBMT reported 62 patients with aggressive NHL undergoing RIT in their series of which a majority had a matched sibling donor [24]. Although chemosensitivity was the only factor predictive of outcome by multivariate analysis, patients with aggressive subtypes had only a 32% 1-year PFS, which was inferior to patients with indolent histologies. A multicenter report from the United Kingdom showed similar results in a smaller group of patients; the relapse risk was higher for aggressive NHL compared to low-grade lymphomas (67.9 vs. 10%, p = 0.014) [14]. This translated into a dismal 16% EFS at 2 years. Finally, Morris and colleagues showed that patients with high-grade lymphomas fared much worse than other subtypes in terms of PFS (34 vs. 65%, p = 0.002), overall survival (34 vs. 73%, p < 0.001), and TRM (relative risk, 2.3; p = 0.02). Reasons for increased toxicity in the aggressive group were unexplained [15]. However, not all series have found aggressive histology to be a negative predictive factor. Dean and colleagues compared 13 patients with DLCL to 12 patients with follicular lymphoma (and 4 patients with mantle cell lymphoma), who received a uniform salvage regimen prior to RIT [34]. Chemosensitivity to the salvage regimen was the most important predictor of outcome, and histology did not correspond to either EFS or OS in this small study. The poorer results seen with aggressive NHL patients undergoing myeloablative alloHCT can be partially attributed to patient selection and intensive prior therapies. Most DLCL patients are offered autoHCT at the time of initial relapse due to its proven efficacy and low TRM (<5% in most series). Thus, by the time an allogeneic approach is considered, many patients have already failed a high-dose regimen. Myeloablative alloHCT in this setting is highly toxic and patients failing a prior autoHCT are typically not candidates for fully ablative regimens. In contrast, RIT may be a feasible salvage option. Studies evaluating RIT in patients with aggressive NHL failing a prior autoHCT, however, have shown mixed results. Escalon and colleagues from the M.D. Anderson Cancer Center presented pilot data on 20 patients with NHL relapsing after a prior autoHCT, including 10 with DLCL [35]. Most patients had minimal disease burden and a good performance status. Using fludarabine, cyclophosphamide, and rituximab, the authors showed an encouraging 95% 3-year PFS with a median follow-up of 25 months. These results are tempered, however, by two other studies of RIT of patients relapsing following autoHCT. Branson and colleagues used fludarabine, melphalan, and alemtuzumab conditioning in a heterogeneous group of NHL patients (10 with high-grade NHL) and demonstrated PFS and OS of 50 and 53%, respectively, with a median follow-up of 14 months [36]. The FHCRC reported a 3-year PFS and OS of 28 and 31%, respectively, with no plateau in terms of relapse in a group of 147 patients (including 24 with aggressive NHL) treated with fludarabine and low-dose TBI. The presence of acute GVHD increased toxicity but did not confer benefit, whereas chronic GVHD correlated with improved PFS. It should be emphasized that each of these studies offered RIT to patients relapsing after a prior autoHCT; others have proposed a “consolidative” RIT immediately following autoHCT which may have more optimistic results [37, 38]. We await mature data on these approaches.

Chapter 8  Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning 

Although inferior to results in patients with indolent histologies, some patients with aggressive lymphoma clearly benefit from RIT. A summary of current series, as discussed above, demonstrates that up to one-third of patients may enjoy long-term disease control. RIT for selected patients with aggressive lymphoma should be considered in patients who have failed a prior autoHCT, have an acceptable performance status, and have an appropriate matched sibling or matched URD. However, demonstration of chemosensitivity by either standard CT criteria or metabolic criteria prior to transplantation is essential [39].

6.  T-cell Lymphoma T-cell lymphomas (T-NHL) comprise approximately 10% of all NHL, and include a diverse group of clinicopathologic entities. The most common nodal subtype is peripheral T-cell lymphoma, unspecified, which accounts for nearly 50% of T-NHL and typically has an aggressive course. The remaining histologies include a diverse group of extranodal and nodal disorders, including cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF), angioimmunoblastic lymphoma (AILD), and anaplastic large cell lymphoma (ALCL). In general, T-NHL is characterized by drug resistance and inevitable relapse in the vast majority of subtypes. Much of the historical treatment approach for T-NHL has been extrapolated from data in B-cell NHL, but this is clearly suboptimal as the adverse significance of T-cell phenotype as compared to B-cell phenotype is well-established [40–42]. AutoHCT as part of front-line management is more promising than when offered at relapse as the long-term disease control rate is only ~30% in the salvage setting [3, 43, 44] (Table 8-3). There is now increasing evidence that T-NHL is susceptible to a GVL effect, and the literature is peppered with optimistic case reports and small series [45–48]. An early study by Rodriguez and colleagues from MDACC evaluated 29 patients undergoing autoHCT and 7 patients undergoing fully ablative alloHCT [43]. Although the OS was not different in the two groups, the main cause for treatment failure in the allogeneic group was toxicity and four of five patients died in CR. Reduced intensity approaches, as outlined above, may decrease the high TRM and capitalize on GVL effects. An Italian group recently reported on 17 patients with either relapsed or refractory T-NHL undergoing nonmyeloablative alloHCT [46]. All patients were heavily pretreated, and all had unfavorable histologies including alk-negative ALCL, angioimmunoblastic T-NHL, and peripheral T-NHL unspecified. This is one of the few prospective phase II studies on alloHCT for T-NHL and reported an impressive 3-year OS and PFS of 81 and 64%, respectively. This same group also retrospectively compared 11 patients with relapsed T-NHL undergoing autoHCT to 8 patients undergoing nonmyeloablative alloHCT; only one-third of autoHCT patients remained in remission at 3 years, whereas all 8 allogeneic patients remained in remission at 1.5 years [49]. Given the heterogeneity of T-NHL, it is likely that some subtypes will fare better than others in terms of GVL and outcome following RIT. One common subtype of T-NHL is cutaneous T-cell lymphoma, which includes mycosis fungoides/Sezary syndrome (MF/SS) and primary cutaneous ALCL. Investigators from the City of Hope reported on eight patients with heavily pretreated MF/ SS undergoing allogeneic stem cell transplant, including four patients receiving

117

26

4

3

7

Italian multicentera 2004, 2005 [46, 68]

City of Hopeb 2005 [47]

Italian multicenterc 2003 [69]

City of hoped 2006 [2]

Flu-mel

51 yo (20–67)

Flu-mel

NS

MRD URD

1 MRD 3 URD

57

67 (2/3)

75

51

DFS/PFS Stem cell source (%)

Flu-cy-thiotepa 22 MRD 3 MRD (mismatched) 1 URD

Preparative regimen

37, 47, 56 yo Flu-cy-TBI

46 yo (21–59)

45 yo (15–64)

Median age (range)

57

67 (2/3)

75

61

NS

1.5,2+

4.5+

2+

Follow up OS (%) (yrs)

  65

100

   0

  28

NS

NS

0

NS

Acute Relapse GVHD (%) (%)

28

33

25

13

TRM (%)

Flu fludarabine, PFS/EFS progression free survival/event free survival, OS overall survival, yrs years, TBI total body irradiation, MRD matched related donor, URD unrelated donor, TRM treatment-related mortality, NS not specified, GVHD graft-versus-host disease a  All patients had systemic T-NHL (either PTCL, AILD, or ALCL) b  All four patients had CTCL/MF c  All patients had CTCL/MF d  Four patients had CTCL/MF and three had PTCL

n

Group/year

Table 8-3.  Allogeneic nonmyeloablative/reduced intensity transplantation for T-NHL.

118  S.M. Smith and G.G. Laport

Chapter 8  Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning 

a reduced intensity preparative regimen. All patients achieved a CR and six remain in remission with nearly 5 years follow-up time, including three patients undergoing RIT. Of note, three of the four patients undergoing RIT had URD, and only one died of transplant-related complications [47]. The management of relapsed T-NHL remains problematic, but the available literature supports allogeneic approaches as a promising avenue. The heterogeneity and rarity of T-NHL will likely mandate a multicenter and collaborative effort to better understand the role of RIT. 6.1.  Novel/Emerging Therapies 6.1.1.  Alemtuzumab As with myeloablative regimens, there appears to be little consensus on the optimal conditioning regimen for reduced intensity transplants for NHL, but most groups combine fludarabine with alkylating agents, and occasionally use TBI. Alemtuzumab (Campath-1H), a monoclonal antibody directed against CD52, is a potent immunosuppressant that provides in vivo T-cell depletion. Alemtuzumab is increasingly being used in reduced intensity regimens due to early evidence of decreased acute GVHD and a potentially lower early TRM; however, an increase in CMV reactivation has been observed. This is usually managed with pre-emptive antiviral agents (i.e., valganciclovir) and close monitoring via CMV PCR [50]. Although less commonly seen in alemtuzumabcontaining versus anti-thymocyte globulin (ATG)-containing regimens, EBV reactivation may also occur [51, 52]. The main beneficial effect of alemtuzumab appears to be a decrease in acute GVHD. In a series of 44 patients with refractory hematologic malignancies who received fludarabine, melphalan, and alemtuzumab, no patient developed grade III or IV acute GVHD, and only 5 patients developed any GVHD [53]. Only one patient had chronic GVHD. A separate study of 38 patients by the same group focusing on malignant lymphomas likewise showed no cases of grade III or IV GVHD [36]. However, 18 of 24 CMV-seropositive patients (or those with CMV-seropositive donors) in this study had evidence of CMV reactivation by PCR techniques. Although only one of these patients developed clinical CMV infection, an increase in CMV-associated diseases due to alemtuzumab must be carefully considered. A multicenter comparison of two prospective trials using a nonmyeloablative regimen, one with alemtuzumab and one without alemtuzumab, confirmed these findings [54]. In this study of 129 patients with lymphoproliferative disorders, the incidence of acute and chronic GVHD was significantly lower in the alemtuzumab-containing regimen (21.7 vs. 45.1%, p = 0.006) whereas CMV reactivation almost entirely occurred in the patients receiving alemtuzumab (85 vs. 24%, p < 0.001). There was no difference in either DFS or OS between the two regimens, but relapse was a more frequent cause of death (60 vs. 20%) in patients receiving alemtuzumab. The impact of alemtuzumab on recurrence rates is an important outcome to keep in mind for ongoing and future evaluations of this compound in the transplant setting. Since alemtuzumab appears to significantly decrease the incidence and severity of acute GVHD, it is also being investigated in the URD transplantation setting where the risk of GVHD is prohibitive for many patients. A report of 47 patients, including 20 patients with malignant lymphomas, showed a notably

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low 6.4% rate of severe grade III GVHD; no patients had grade IV GVHD and no patients have died of GVHD with a median follow-up of almost 1 year [55].The overall rate of acute GVHD was 21%. More than 60% of patients had evidence of CMV reactivation, but only one patient died from CMV disease. Thus, the potent immunosuppressive effects of alemtuzumab may allow alternative donor stem cell sources to be more safely used and thereby broaden the applicability of alloHCT to patients without a matched sibling donor. In summary, alemtuzumab decreases early GVHD-related complications, but its impact on disease control remains to be established. Viral reactivation is common, but can be managed in most patients with close monitoring and preemptive therapy. Maribivir is an antiviral agent in clinical development that is a selective UL 97 viral protein-kinase inhibitor [56]. Unlike gancyclovir and foscarnet, it does not cause myelosuppression or nephrotoxicity which may help facilitate the use of alemtuzumab. 6.1.2.  Rituximab and Radioimmunotherapy Other monoclonal antibodies may also have utility as part of alloHCT in lymphoma. Rituximab, a chimeric monoclonal antibody directed against CD20, is nearly universally applied in patients with B-cell malignancies. Rituximab potentiates tumor control, is being explored in settings of minimal residual disease, and provides effective in vivo purging of malignant B-cells. Several investigators have proposed that B-cells are important in the pathogenesis of GVHD since rituximab therapy may be effective in this setting [57]. A small study of ten patients with refractory lymphoid malignancies undergoing alloHCT and treated with early post-transplant rituximab showed no GVHD and retention of efficacy suggesting that GVL effects were maintained [58]. Rituximab has also been directly used to treat refractory chronic GVHD in patients with a variety of hematologic malignancies with 65% of patients demonstrating symptomatic improvement [59]. A new humanized anti-CD20 monoclonal antibody, IMMU-106, has shown activity in relapsed NHL patients and is associated with less infusion reactions compared to rituximab [60]. Gopal and colleagues from the FHCRC found in vitro synergy between cytarabine, fludarabine, and 90Y-ibritumomab tiuxetan (Zevalin®), a radiolabeled monoclonal antibody against CD20 and are conducting an RIT trial with incorporation of this agent for patients with relapsed/refractory B-cell malignancies [61]. These observations of both disease and GVHD control are provocative and warrant ongoing investigations of anti-CD20 directed therapies in the post-allogeneic transplant setting, either as treatment of minimal residual disease or as immunomodulation of GVL and GVHD. Other agents in development include epratuzumab, a humanized anti-CD22 monoclonal antibody, that has induced responses in NHL patients as a single agent and in combination with chemotherapy [62]. CD22 is a B-cell restricted marker expressed late in the stages of differentiation and demonstrates >90% expression in both large B-cell lymphomas and follicular lymphomas. A novel class of targeted therapies are small modular immunopharmaceuticals (SMIP) with CD37-SMIP demonstrating impressive in  vitro cytotoxicity against B-cell leukemia/lymphoma cell and chronic lymphocytic leukemia lines [63]. CD37 is a lineage-specific B-cell antigen strongly expressed on B cells and transformed mature B-cell leukemia and lymphoma cells. In summary, several promising monoloconal antibodies with activity against B-cell NHL are in various phases of development and show great potential thus far.

Chapter 8  Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning 

7.  Conclusions Reduced intensity conditioning regimens followed by alloHCT are increasingly utilized in patients with relapsed NHL. RIT is feasible and the less intensive regimens, with or without alemtuzumab, have expanded the number of patients who may be considered for alloHCT. As seen in myeloablative HCT, patients with early stage, good-risk disease, and/or who demonstrate chemosensitivity stand to benefit the most from this treatment modality. Patients with rapidly proliferating NHL subtypes should be carefully selected as disease control prior to RIT is essential. Many questions remain, including (1) what is the optimal conditioning regimen (2) how can GVL be amplified while minimizing GVHD risk and (3) how can patient selection be optimized. In summary, RIT is a promising approach in both the frontline and salvage setting for a growing number of NHL patients and ongoing studies are warranted.

References 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66 2. Rodriguez R, Nademanee A, Gruel N et al (2006) Comparison of reduced-intensity and conventional myeloablative regimens for allogeneic transplantation in nonHodgkin’s lymphoma. Biol Blood Marrow Transplant 12:1326–1334 3. van Besien K, Loberiza FR Jr, Bajorunaite R et al (2003) Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102:3521–3529 4. Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP (2005) New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447–8452 5. Kaminski MS, Tuck M, Estes J et  al (2005) 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441–449 6. Rohatiner AZ, Nadler L, Davies AJ et al (2007) Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: Long-term follow-up. J Clin Oncol 25:2554–2559 7. Schouten HC, Qian W, Kvaloy S et al (2003) High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918–3927 8. Forstpointner R, Dreyling M, Repp R et al (2004) The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:3064–3071 9. Hiddemann W, Kneba M, Dreyling M et al (2005) Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advancedstage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725–3732 10. Vigouroux S, Michallet M, Porcher R et  al (2007) Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica 92:627–634 11. Khouri IF, Saliba RM, Giralt SA et al (2001) Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence

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S.M. Smith and G.G. Laport of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98:3595–3599 12. Khouri IF, Saliba RM, Hosing C et al (2005) Autologous stem cell transplantation vs. non-myeloablative allogeneic transplantation after high-dose rituximab-containing regimens for relapsed chemosensitive follicular lymphoma. Blood 106:19a 13. Cutler C, Miklos D, Kim HT et al (2006) Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108:756–762 14. Faulkner RD, Craddock C, Byrne JL et al (2004) BEAM-alemtuzumab reducedintensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients. Blood 103:428–434 15. Morris E, Thomson K, Craddock C et  al (2004) Outcomes after alemtuzumabcontaining reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood 104:3865–3871 16. Van Besien K, Carrereras J, Zhang MJ et al (2005) Reduced intensity vs. myeloablative conditioning for HLA matched sibling transplantation in follicular lymphoma. Blood 106:167a abstract 561 17. Solal-Celigny P, Roy P, Colombat P et al (2004) Follicular lymphoma international prognostic index. Blood 104:1258–1265 18. Dave SS, Wright G, Tan B et  al (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351:2159–2169 19. Kauh J, Baidas SM, Ozdemirli M, Cheson BD (2003) Mantle cell lymphoma: Clinicopathologic features and treatments. Oncology (Williston Park) 17:879–891 20. Mangel J, Leitch HA, Connors JM et al (2004) Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: a matched pair analysis. Ann Oncol 15:283–290 21. Vandenberghe E, Ruiz de Elvira C, Loberiza FR et al (2003) Outcome of autologous transplantation for mantle cell lymphoma: A study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries. Br J Haematol 120:793–800 22. Corradini P, Tarella C, Olivieri A et al (2002) Reduced-intensity conditioning followed by allografting of hematopoietic cells can produce clinical and molecular remissions in patients with poor-risk hematologic malignancies. Blood 99:75–82 23. Ganti AK, Bierman PJ, Lynch JC, Bociek RG, Vose JM, Armitage JO (2005) Hematopoietic stem cell transplantation in mantle cell lymphoma. Ann Oncol 16:618–624 24. Robinson SP, Goldstone AH, Mackinnon S et al (2002) Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: An analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100:4310–4316 25. Avivi I, Canals C, Taghipour G et  al (2006) Matched unrelated donor stem cell transplantation for relapsed or refractory mantle cell lymphoma. A retrospective analysis from the EBMT Lymphoma Working Party. Blood 108:602 abstract 26. Maris MB, Sandmaier BM, Storer BE et al (2004) Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood 104:3535–3542 27. Khouri IF, Saliba RM, Okoroji GJ, Acholonu SA, Champlin RE (2003) Long-term follow-up of autologous stem cell transplantation in patients with diffuse mantle cell lymphoma in first disease remission: The prognostic value of beta2-microglobulin and the tumor score. Cancer 98:2630–2635 28. Blay J, Gomez F, Sebban C et al (1998) The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood 92:3562–3568

Chapter 8  Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning  29. Caballero MD, Perez-Simon JA, Iriondo A et al (2003) High-dose therapy in diffuse large cell lymphoma: Results and prognostic factors in 452 patients from the GELTAMO Spanish Cooperative Group. Ann Oncol 14:140–151 30. Peniket AJ, Ruiz de Elvira MC, Taghipour G et  al (2003) An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: Allogeneic transplantation is associated with a lower relapse rate but a higher procedurerelated mortality rate than autologous transplantation. Bone Marrow Transplant 31:667–678 31. van Besien K, Thall P, Korbling M et  al (1997) Allogeneic transplantation for recurrent or refractory non-Hodgkin’s lymphoma with poor prognostic features after conditioning with thiotepa, busulfan, and cyclophosphamide: Experience in 44 consecutive patients. Biol Blood Marrow Transplant 3:150–156 32. Dhedin N, Giraudier S, Gaulard P et al (1999) Allogeneic bone marrow transplantation in aggressive non-Hodgkin’s lymphoma (excluding Burkitt and lymphoblastic lymphoma): A series of 73 patients from the SFGM database. Societ Francaise de Greffe de Moelle. Br J Haematol 107:154–161 33. Doocey RT, Toze CL, Connors JM et al (2005) Allogeneic haematopoietic stemcell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma. Br J Haematol 131:223–230 34. Dean RM, Fowler DH, Wilson WH et  al (2005) Efficacy of reduced-intensity allogeneic stem cell transplantation in chemotherapy-refractory non-hodgkin lymphoma. Biol Blood Marrow Transplant 11:593–599 35. Escalon MP, Champlin RE, Saliba RM et al (2004) Nonmyeloablative allogeneic hematopoietic transplantation: A promising salvage therapy for patients with nonHodgkin’s lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol 22:2419–2423 36. Branson K, Chopra R, Kottaridis PD et al (2002) Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol 20:4022–4031 37. Carella AM, Cavaliere M, Lerma E et  al (2000) Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. J Clin Oncol 18:3918–3924 38. Dey BR, McAfee S, Sackstein R et  al (2001) Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation. Biol Blood Marrow Transplant 7:604–612 39. Cheson BD, Pfistner B, Juweid ME et  al (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586 40. Melnyk A, Rodriguez A, Pugh WC, Cabannillas F (1997) Evaluation of the Revised European–American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin’s lymphoma. Blood 89:4514–4520 41. Gisselbrecht C, Gaulard P, Lepage E et  al (1998) Prognostic significance of T-cell phenotype in aggressive non-Hodgkin’s lymphomas. Groupe d’Etudes des Lymphomes de l’Adulte (GELA). Blood 92:76–82 42. Coiffier B, Brousse N, Peuchmaur M et  al (1990) Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: A prospective study of 361 immunophenotyped patients treated with the LNH-84 regimen. The GELA (Groupe d’Etude des Lymphomes Agressives). Ann Oncol 1:45–50 43. Rodriguez J, Munsell M, Yazji S et al (2001) Impact of high-dose chemotherapy on peripheral T-cell lymphomas. J Clin Oncol 19:3766–3770 44. Song KW, Mollee P, Keating A, Crump M (2003) Autologous stem cell transplant for relapsed and refractory peripheral T-cell lymphoma: Variable outcome according to pathological subtype. Br J Haematol 120:978–985

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S.M. Smith and G.G. Laport 45. Aoyama Y, Yamane T, Hino M et al (2001) Nodal gamma/delta T cell lymphoma in complete remission following allogeneic bone marrow transplantation from an HLA-matched unrelated donor. Acta Haematol 105:49–52 46. Corradini P, Dodero A, Zallio F et  al (2004) Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin’s lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol 22:2172–2176 47. Molina A, Zain J, Arber DA et al (2005) Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides. J Clin Oncol 23:6163–6171 48. Mansour MR, Dogan A, Morris EC et  al (2005) Allogeneic transplantation for hepatosplenic alphabeta T-cell lymphoma. Bone Marrow Transplant 35:931–934 49. Corradini P, Dodero A, Zallio F et al (2002) Nonmyeloablative conditioning followed by allogeneic transplantation has a better outcome than high-dose chemotherapy plus autografting in non-Hodgkin’s lymphoma with T-cell histology. Blood 100:427a 50. Kline J, Pollyea DA, Stock W et  al (2006) Pre-transplant ganciclovir and post transplant high-dose valacyclovir reduce CMV infections after alemtuzumab-based conditioning. Bone Marrow Transplant 37:307–310 51. Cohen J, Gandhi M, Naik P et al (2005) Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning. Br J Haematol 129:229–239 52. Scheinberg P, Fischer SH, Li L et al (2007) Distinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia. Blood 109:3219–3224 53. Kottaridis PD, Milligan DW, Chopra R et  al (2000) In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 96:2419–2425 54. Perez-Simon JA, Kottaridis PD, Martino R et  al (2002) Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood 100:3121–3127 55. Chakraverty R, Peggs K, Chopra R et  al (2002) Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. Blood 99:1071–1078 56. Wade JC (2006) Viral infections in patients with hematological malignancies. Hematology Am Soc Hematol Educ Program 368–374 57. Ratanatharathorn V, Ayash L, Reynolds C et al (2003) Treatment of chronic graftversus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant 9:505–511 58. Shimoni A, Hardan I, Avigdor A et al (2003) Rituximab reduces relapse risk after allogeneic and autologous stem cell transplantation in patients with high-risk aggressive non-Hodgkin’s lymphoma. Br J Haematol 122:457–464 59. Zaja F, Bacigalupo A, Patriarca F et  al (2007) Treatment of refractory chronic GVHD with Rituximab: A GITMO study. Bone Marrow Transplant 40:273–277 60. Morschhauser F, Leonard JP, Coiffier B et al (2005) Initial safety and efficacy of a second-generation humanized anti-CD20 antibody, IMMU-106 (hA20), in nonHodgkin’s lymphoma. Blood 106:683a 61. Gopal AK, Pagel JM, Rajendran JG et al (2006) Improving the efficacy of reduced intensity allogeneic transplantation for lymphoma using radioimmunotherapy. Biol Blood Marrow Transplant 12:697–702 62. Stein R, Qu Z, Chen S et al (2004) Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and Its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin’s lymphoma. Clin Cancer Res 10:2868–2878

Chapter 8  Non-Hodgkin’s Lymphoma: Allogeneic Reduced Intensity Conditioning  63. Zhao X, Lapalombella R, Joshi T et al (2007) Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical. Blood 110:2569–2577 64. Maris MB, Sandmaier BM, Storer B et  al (2005) Allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning for relapsed or refractory follicular lymphoma. Blood 106:329a 65. Kusumi E, Kami M, Kanda Y et al (2005) Reduced-intensity hematopoietic stemcell transplantation for malignant lymphoma: A retrospective survey of 112 adult patients in Japan. Bone Marrow Transplant 36:205–213 66. Robinson SP, Schmitz N, Taghipour G, Sureda A (2004) Reduced intensity allogeneic stem cell transplantation for mantle cell lymphoma is associated with substantial late transplant related mortality and a poor outcome in patients with chemoresistant disease. Blood 104:865–872 67. Khouri IF, Lee MS, Saliba RM et al (2003) Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol 21:4407–4412 68. Corradini P, Dodero A, Bregni M et al (2005) Reduced-intensity conditioning followed by allogeneic stem cell transplantation for relpapsed lymphohas: Impact of pre-transplantation factors on long-term outcome. Blood 106 69. Soligo D, Ibatici A, Berti E et al (2003) Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen. Bone Marrow Transplant 31:663–666

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Chapter 9 The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults Heidi D. Klepin and David D. Hurd

1.  Introduction Multiple myeloma is a disease of the elderly. Survival outcomes remain unacceptably low in older adults with multiple myeloma. To date, no obvious difference in tumor biology has been elucidated to explain the survival disparity between older and younger patients. Multiple factors including comorbidity, performance status, decreased physiologic reserve, and potentially undertreatment contribute to poor outcomes in elderly patients with myeloma. Allogeneic stem cell transplantation remains the only curative treatment for multiple myeloma to date. Use of allogeneic transplantation in older adults remains limited due to high associated morbidity and mortality. Recently, traditional upper age limits for transplantation have been questioned, along with the definition of “elderly” itself. Multiple challenges will need to be met to advance the role of allogeneic transplantation into the treatment paradigm for older adults. These challenges include (1) optimizing conditioning regimens, (2) decreasing graft versus host disease (GVHD), (3) optimizing donor selection, and (4) optimizing patient selection.

2.  Myeloma and Age Multiple myeloma is a disease of the elderly with a median age of 70 years reported in the SEER database from 1997 to 2001 [1]. The incidence of multiple myeloma increases with age (Fig. 9-1). The number of elderly patients with myeloma is expected to increase with the aging of the US population translating into more complex and challenging treatment decisions in clinical practice. Age has a negative impact on prognosis in multiple myeloma in unselected populations. The SEER registry statistics from 1995 to 2001 report 5-year relative survival rates of 42.9 and 25.2% for patients <65 and ³65 years of age, respectively (SEER website). Survival is dramatically decreased in the ³75-year old population. In a retrospective review of 1,027 patients with newly diagnosed multiple myeloma evaluated at the Mayo Clinic, Kyle et al. reported a median age of 66 years with 38% of patients ³70 years of age [2]. From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_9, © Springer Science + Business Media, LLC 2003, 2010

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Fig. 9-1.  Age-specific SEER incidence rates for multiple myeloma 1998–2002. SEER surveillance epidemiology and end results. http://seer.cancer.gov/

The median duration of survival was 40.5 months for patients younger than 70 years and 26.4 months for those 70 years and older. In multivariate analysis, age remained one of the most important negative prognostic factors. To date, no clear differences in the biology of disease due to age have been elucidated in multiple myeloma. Several studies have reported no significant differences in older patients with regard to presenting biologic features including hematologic parameters, stage of disease, beta 2 microglobulin level, or renal function [3–5]. There is no evidence that clinically significant cytogenetic abnormalities are age dependent [6]. Available evidence, therefore, does not support the idea that older patients have more aggressive disease. The negative impact of age on prognosis was reviewed by Mileshkin et al. and related to a combination of patient-specific factors including decreased physiologic reserve, comorbidity, performance status, social support, referral bias, and potentially, undertreatment [7]. There are multiple physiologic changes associated with “normal” aging which can impact tolerance to the stress of tumor burden and treatment. These include altered immune function, changes in drug metabolism, and changes in organ function (i.e., decreased glomerular filtration rate, decreased cardiac output, decreased resting PAO2, decreased muscle mass). The degree to which any individual patient experiences age-related physiologic changes varies significantly and cannot accurately be measured by chronologic age alone.

Chapter 9  The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults 

In addition to subclinical changes in organ function, older adults are more likely to present with measurable comorbid disease. Significant concurrent comorbidity was recorded in 33.8% of patients in an unselected cohort aged 70 and above with newly diagnosed multiple myeloma [5] and likely plays a large role in treatment decisions and toxicity. Poor functional status (ECOG performance status score ³2) is more common in older patients with multiple myeloma and is independently associated with decreased survival [2, 5]. The impact of inadequate social support, referral bias, and treatment bias can be speculated but have not yet been studied in this population. Despite the negative impact of age on prognosis in unselected populations, there have been multiple small studies which have reported equivalent response to therapy and survival rates for selected older patients compared to younger patients treated with similar therapies including autologous stem cell transplantation [4, 8–11]. Most of these analyses were conducted on selected patients who were enrolled on clinical trials. These reports of equal benefit from equal treatment in a selected elderly population have resulted in increased interest in pursuing more aggressive therapies in older patients in an attempt to improve survival outcomes. In this context, an exploration of the role of potentially curative allogeneic transplantation becomes a reasonable question for older adults with myeloma. It is important, however, to carefully refine the definition of “older” in the transplant setting. The unacceptably high treatment-related toxicity (53%) documented for previously untreated myeloma patients £55 years of age who received myeloablative allogeneic transplantation on the US Intergroup Trial S9321 raises significant concerns that certain aggressive treatments will be prohibitively toxic in older adults [12]. It is unlikely that myeloablative allogeneic transplantation will be explored in adults >70 years of age. This study, however, did support the notion of curability with myeloablative allogeneic transplantation due to documented long-term survival. It is unclear whether treatment toxicity would be decreased if this trial were repeated with modern supportive care strategies. Recent advances including reduced intensity conditioning (RIC), use of peripheral blood stem cells, sophisticated GVHD prophylaxis regimens, and improved supportive care may pave the way for extension of allogeneic transplantation techniques in to the young–old population which has until recently been excluded.

3.  Trends in Allogeneic Transplantation by Age Allogeneic transplantation has traditionally been restricted in clinical trials and practice to younger adults due to concerns regarding increased toxicity with age. Many centers have used age limits of 50 or 55 years. In recent years upper age limits have been challenged. Worldwide the number of allogeneic transplantations being performed has increased. The number of allogeneic transplantations in adults over the age of 50 continues to increase as well (Fig. 9-2). According to the Center for International Blood and Marrow Transplant Research (CIBMTR), between the years 2002 and 2006 35% of allograft recipients were above the age of 50. These trends can be expected to continue as many of the common indications for allogeneic transplantation including acute myelogenous leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, non-Hodgkin’s lymphoma, and multiple myeloma are most commonly diagnosed in older adults.

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H.D. Klepin and D.D. Hurd

100

80

Transplants, %

130 

≤ 20 yrs 21-40 yrs 41-50 yrs 51-60 yrs > 60 yrs

60

40

20

0

1987-1992

1993-1999

2000-2006

Fig.  9-2.  Trends in allogeneic transplantation by recipient age from 1987 to 2006.* Data acquired from the Center for International Blood and Marrow Transplant Research (CIBMTR).* Transplants for acute myelogenous leukemia, acute lymphocytic leukemia, and chronic myelogenous leukemia

4.  The Influence of Age on Myeloablative Allogeneic Transplantation Age is one of the most commonly used eligibility criteria for allogeneic transplantation. Multiple early studies have suggested a negative association between increasing age and outcomes with conventional myeloablative transplantation regimens used to treat various hematologic malignancies [13–15]. Many of these initial studies included patients younger than 20 raising suspicions that the improved outcomes associated with younger age were most attributed to inclusion of pediatric patients. The question of an upper age limit for transplantation has more recently been investigated in cohorts of adult patients using age cutoffs of 50 years or greater (Table 9-1). The majority of these studies are retrospective, single institution studies with relatively small numbers of patients >50 years of age represented. Of the single institution studies represented, 5 reported favorable outcomes in adults over 50 years of age while 4 reported increased treatment-related mortality (TRM) or decreased overall survival associated with age [16–24]. Two larger multi-institution retrospective studies have addressed this issue. Ringden et al. evaluated the outcome of 2,180 transplants for leukemia from 138 institutions reported to the International Bone Marrow Transplant Registry (IBMTR) [25]. Outcomes were analyzed by the following age groups: 30–39 years, 40–44 years, 45–49 years, and 50 years of age or older. The incidence of leukemia free survival, GVHD, and relapse were comparable between the age cohorts. TRM at 2 years was higher for those aged >45 years with advanced leukemia. The largest multi-center study to investigate the influence of age on myeloablative transplantation was reported by the Japan Society for Hematopoietic Stem Cell Transplantation [26]. In this study 5,127 patients

1986

1993

1993

1998

1998

2000

2002

2003

2004

2005

2006

Klingemann et al. [23]

Ringden et al. [25]

Clift et al. [16]

Du et al [20]

Hansen et al. [22]

Deeg et al. [18]

De la Camara et al. [17]

Farag et al. [21]

Yanada et al. [26]

Wallen et al. [24]

Ditschkowski et al. [19]

MSD

MSD

MSD/syngeneic

Donor

Various

Various

Various

Various

Various

MDS

CML

MSD/MUD

MSD

MSD/MUD

MSD

MSD

MSD/MUD

MUD

AML/MDS MSD/MUD

CML

Leukemia

Leukemia

Disease

215

52

5,147

313

129

50

196

436

33

2,180

63

Total N

215

  52

398

  52

  32

  50

  13

  59

  33

  80

  13

N > 50 years

Allogeneic transplantation is feasible in age >50

Allogeneic transplantation feasible in age >60

Age >50 was associated with increased TRM and decreased OS

Age >50 associated with increased TRM in patients with high risk disease only

No difference in GVHD, TRM, OS in age >50

Allogeneic transplantation feasible in age >55

Age >50 associated with decreased OS

No difference in OS and GVHD. Age >50 associated with increased TRM compared to age <40

Patients >50 had comparable survival to younger patients

No difference in OS, DFS, GVHD by age group. Patients >45 with advanced leukemia had increased TRM

Age >50 associated with increased GVHD, TRM, and decreased OS

Comments

CML chronic myelogenous leukemia, AML acute myelogenous leukemia, MDS myelodysplastic syndrome, MSD matched sibling donor, MUD matched unrelated donor, GVHD graft versus host disease, TRM treatment related mortality, OS overall survival, DFS disease free survival

Year

Author (reference)

Table 9-1.  Myeloablative allogeneic transplantation for patients above age 50.

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treated for various hematologic malignancies were analyzed, including 389 patients above age 50. Age above 50 was found to be independently associated with TRM and decreased overall survival. Estimated 1-year TRM was 34.7 and 22.7% in the older and younger groups, respectively. The probability of overall survival at 4 years was 35.6% for patients over 50 and 53.5% for those younger than 50.

5.  Potential Barriers to Allogeneic Transplantation in Older Adults There are multiple potential barriers to successful allogeneic transplantation in older adults. These include concerns relate to the toxicity of the preparative regimens, GVHD, donor availability, and patient selection. Optimizing the preparative regimens to maximize efficacy but minimize morbidity is critical to successful transplantation in older adults. There are no prospective studies comparing preparative regimens in older adults. Retrospective data suggest that regimens containing total body radiation may increase TRM in this population [26]. RIC regimens designed to minimize the toxicity of myeloablation have been explored in older adults and will be discussed in the next section. GVHD represents another potential barrier to transplantation in the elderly and has been identified as a major contributing factor to transplant-related mortality in older adults [19]. Increasing age has been identified as a risk factor for development of acute GVHD [27, 28]. Analysis of 2,036 recipients of HLA-identical sibling transplants from the IBMTR demonstrated an increased risk for acute GVHD in older patients. The age gradient was modest and the association was no longer significant after excluding female-to-male transplants [27]. Similar findings were reported by Weisdorf et  al. using an age cutoff of 18 while analyzing 469 patients with histocompatible sibling donors at a single institution [28]. The question of whether increasing age poses an incremental increased risk is unclear. One study supports an increased risk of acute GVHD in adults >50 years of age compared to younger adults [23] while others do not [20–22]. There is some evidence, however, that age is associated with increased severity of acute GVHD [29]. Several studies have also documented an increase in chronic GVHD associated with increasing age [30–32]. Analysis of 2,534 recipients of HLA-identical sibling transplants conducted by the IBMTR showed that the strongest risk factor for chronic GVHD was a history of acute GVHD [30]. When patients with a history of acute GVHD were excluded, age over 20 years became an independent risk factor. Again the question of incremental risk with increasing age remains unclear. There are conflicting results from single institution studies regarding the impact of age >50 years on risk of chronic GVHD [20–23]. A study from Aschan et  al. of 182 leukemia patients reported that adults >30 years benefited more significantly from double GVHD prophylaxis than younger patients with decreased chronic GVHD and improved survival [33]. Continued advances in GVHD prophylaxis will likely improve transplant outcomes in older adults. Donor availability represents another potential obstacle in allogeneic transplantation for older adults. The possibility of finding a matched family donor

Chapter 9  The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults 

tends to be lower in older adults due to aging of the family. Matched sibling donors are also likely to be older which is associated with an increased risk of developing acute GVHD and potentially increased TRM [34, 35]. Additional evidence regarding the significance of increased donor age comes from the National Marrow Donor Program. Analysis of 6,978 unrelated-donor marrow transplantations showed that increasing donor age was independently associated with increased risk of GVHD and decreased overall survival [36]. Optimal donor selection for older adults is unclear and may require investigation of the potential trade-off between use of older sibling grafts and younger matched unrelated grafts. Advances in HLA matching using high-resolution typing result in improved survival in unrelated donor transplantation [37] and may translate into improved options and outcomes for older adults. Finally, patient selection remains a major obstacle in myeloablative transplantation for older adults. There are two issues related to patient selection to consider in this context. The first relates to disease status and the second relates to the fitness of the individual patient. It is clear from retrospective studies that transplantation in earlier stages of disease results in superior outcomes for adults >50 years of age [19, 21]. One study of 215 adults >50 years of age who underwent myeloablative allogeneic transplantation for either early (41%) or advanced (59%) hematologic malignancies reported significantly decreased TRM and improved overall survival in the early stage group [19]. The timing of transplantation remains an unresolved issue particularly in the setting of multiple myeloma where multiple treatment options are now available. Finally, a systematic approach to the assessment of biologic age has not yet been developed making selection of “fit” older adults a challenge in the clinical setting. Older adults represent a heterogeneous population. They are more likely to present with diagnosed comorbid disease [5, 38, 39] or may have subclinical changes in organ function resulting in decreased physiologic reserve. Age-related changes in drug metabolism may also impact toxicity risk. The development of evidence-based patient selection algorithms to identify older adults who are most likely to tolerate and benefit from allogeneic transplantation is critical to successful application of this modality to an older population.

6.  Reduced Intensity Conditioning Transplantation RIC or non-myeloablative allogeneic transplantation approaches were designed to achieve engraftment without marrow ablation. This method may be efficacious in settings where the graft versus tumor effect is sufficient to eradicate or control underlying disease. Due to the non-myeloablative approach this method has been investigated in patients who would have been considered ineligible for traditional myeloablative transplantation including older adults. Data from the CIBMTR demonstrate that the majority of RIC transplants reported in 2005–2006 were performed in adults >50 years of age (Fig. 9-3). Multiple retrospective studies have compared outcomes between standard myeloablative conditioning and RIC regimens. Overall there appears to be a decrease in TRM and in the incidence of GVHD favoring the reduced intensity regimens despite increased comorbidity in many of the RIC patients [40–50]. The difference in overall survival appears less clear due in part to an increased risk of relapse seen with RIC particularly in the setting of leukemia [41, 44].

133

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H.D.Age Klepin and D.D.ofHurd Distribution Patients Receiving Allogeneic Transplants by Conditioning Regimen Intensity, 2005-2006

<20y

1,999

425

20-29y

1,130

30-39y

1,125

40-49y 50-59y

279

318

1,449

624

1,336

1,190

60-69y

1,004

213

£70y

3

2400 2000 1600 1200 800

Myeloablative

400

0

51 0

400

800

1200

1600

Reduced Intensity

Fig. 9-3.  Age distribution of patients receiving allogeneic transplants by conditioning regimen intensity, 2005– 2006. Data acquired from the Center for International Blood and Marrow Transplant Research (CIBMTR)

Reduced intensity regimens have been explored to a limited extent in adults over age 60. Multiple small series have reported favorable rates of engraftment, chimerism, TRM, and GVHD in this age group [39, 51–54]. Some of these studies reported no differences in outcome between related and matched unrelated transplants using RIC regimens [53, 54]. The impact of age on outcome was evaluated in two larger series using RIC transplantation [55, 56]. Gomez-Nunez et al. evaluated the results of 145 patients ineligible for myeloablative transplantation who underwent RIC transplantation from a matched sibling over a 3-year period [56]. The median age was 54. Multivariate analyzes found decreased overall survival and increased TRM in adults >60 years of age. Additional negative prognostic factors included prior autologous transplant and Eastern Cooperative Oncology Group Performance Score >1. Alternatively, Corradini et  al. compared outcomes of 90 patients younger than 55 years with 60 patients older than 60 years who were treated with RIC transplantation from a sibling donor [55]. There was no difference in TRM or overall survival between the two groups. However, in the subset of patients who had a prior autologous transplant, older age was associated with increased TRM. Overall, RIC regimens may offer a viable alternative to myeloablative transplantation in selected older adults.

7.  Improving Patient Selection Older patients with hematologic malignancies represent a very heterogeneous population requiring more detailed assessment of health status prior to treatment

Chapter 9  The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults 

135

determination. Eligibility criteria remain a central issue in future trials focused on older adults particularly with regard to allogeneic transplantation. Chronologic age alone is a poor surrogate marker for tolerance to therapy. Developing a set of measurable clinical characteristics which better reflect physiologic age is necessary to critically evaluate the role of allogeneic transplantation in the heterogeneous older adult population. Comorbidity and functional status represent measurable patient-specific characteristics that can refine evaluation of older adults in clinical trials and practice. Older adults are more likely to present with increased comorbid disease [5, 7]. Comorbidity assessment with the Charlson Comorbidity Index has been shown to be predictive of increased toxicity and mortality in allogeneic transplantation [49, 57]. Sorror et al. refined this index to improve sensitivity and documented the reliability and validity of this tool in allogeneic transplantation (Table 9-2) [58]. The new transplant-specific index showed better survival prediction than the Charlson Comorbidity Index in this population. Low scores on the transplant-specific comorbidity index appear predictive of improved survival in both myeloablative and non-myeloablative transplants and in patients with both low and high risk disease [59]. Similarly, Artz et al.

Table 9-2.  Hematopoietic cell transplantation (HCT)-specific comorbidity index (HCT–CI). Comorbidity

Definition

Score

Cardiac

Coronary artery disease, congestive heart failure, myocardial infarction, EF £ 50%

1

Arrhythmia

Atrial fibrillation or flutter, sick sinus or ventricular arrhythmia

1

Cerebrovascular disease

Transient ischemic attack or cerebrovascular accident

1

Diabetes

Requiring treatment with medication

1

Inflammatory bowel disease

Crohn’s disease or ulcerative colitis

1

Obesity

Body mass index >35 kg/m2

1

Infection

Requiring use of antimicrobial treatment

1

Psychiatric disturbance

Depression or anxiety requiring psychiatric consult or treatment

1

Peptic ulcer

Requiring treatment

2

Hepatic disease (mild)

Chronic hepatitis, bilirubin > ULN to 1.5 X the ULN, or AST/ ALT > ULN to 2.5 X ULN

2

Pulmonary (moderate)

DLCO and or FEV1 66–80% or dyspnea with slight activity

2

Rheumatologic

SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica

2

Renal (moderate/severe)

Serum creatinine >2 mg/dL, on dialysis, or prior renal transplant

2

Prior solid tumor

Treated at any point in patient’s past history, excluding nonmelanoma

3

Hepatic (moderate/severe)

Liver cirrhosis, bilirubin >1.5X ULN, or AST/ALT > 2.5 X ULN

3

Heart valve disease

Except mitral valve prolapse

3

Severe pulmonary

DLCO and/or FEV1 £65% or dyspnea at rest or requiring oxygen

3 Total score

This table was adapted from Ref. [58] EF ejection fraction, ULN upper limit of normal, SLE systemic lupus erythmatosis, RA rheumatoid arthritis, CTD connective tissue disease, DLCO diffusion capacity of carbon monoxide

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reported that a simple scale combining the Kaplan–Feinstein Comorbidity Scale and the Eastern Cooperative Oncology Group Performance Status Scale enabled separation of high and low risk patients with 6-month cumulative incidences of TRM of 50 and 15%, respectively [60]. Prospective assessment of comorbidity using established or transplant-specific indices may provide important information for the development of evidence-based risk stratification in older adults evaluated for allogeneic transplantation. Comorbidity assessment alone may not provide sufficient information regarding the physiologic reserve of older patients. In clinical practice it is apparent that older patients with similar age and comorbidity may differ substantially with regard to functional status. Specific measures of functional status can provide more prognostic information than comorbidity alone in older adults [61]. In older cancer patients, Extermann et al. demonstrated that comorbidity and functional assessment were not well correlated and provided independent information [62]. Careful functional assessment during pretransplant evaluation may provide added information for risk stratification. It will be important to prospectively assess the predictive value of task-specific functional assessment tools such as activities of daily living [63] and instrumental activities of daily living [64]. These self-report measures are able to identify functional impairment in cancer patients with good performance scores on the Eastern Cooperative Oncology Group scale [65]. This added discriminatory capacity may be useful to detect subtle changes reflective of decreased functional reserve. Finally, objective measures of physical performance and cognition may be particularly useful in developing an evaluation protocol for older patients being considered for allogeneic transplantation. Physical performance measures such as walking speed and lower extremity function are predictive of future disability, hospitalizations, and mortality in the geriatric population [66–68]. These objective measures may be sensitive to subclinical disability which could be closely associated with morbidity and mortality outcomes in the setting of allogeneic transplantation.

8.  Applications in Multiple Myeloma Despite the increased use of dose-intensive therapy and autologous transplantation in older patients with multiple myeloma, there remains a dearth of information on the use of allogeneic transplantation in this patient population. Refined assessment of physiologic age may facilitate the evaluation of allogeneic transplantation techniques in the treatment of older adults with multiple myeloma. There is recent evidence which supports a potential role for RIC allogeneic transplantation in multiple myeloma treatment. A prospective study of 162 consecutive patients (median age 55; range 30–65 years) compared RIC allogeneic transplantation from a sibling donor with tandem autologous transplantation in newly diagnosed multiple myeloma [69]. All patients received vincristine, doxorubicin, and dexamethasone followed by high-dose melphalan with autologous stem cell rescue. After recovery, patients with an

Chapter 9  The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults 

HLA-identical sibling underwent non-myeloablative allogeneic transplantation. Patients without an HLA-matched sibling underwent a second autologous transplant. Overall survival was 80 months versus 54 months (p = 0.01) favoring the allograft group. Among patient who completed their assigned treatments, TRM was not significantly different between the two groups while disease-related mortality was higher in the double autologous transplant group. These findings suggest that allogeneic transplantation may offer longer term disease control for selected fit patients with multiple myeloma. However, this conclusion should be interpreted with caution due to the disproportionately poor outcomes seen in the tandem autologous transplant arm compared to other published studies. It is currently unclear which older adults might benefit from allogeneic transplantation and where transplantation fits in the sequencing of treatment options currently available. Additional clinical trials are underway evaluating tandem autologous transplantation followed by RIC transplantation for multiple myeloma. Similarly, the BMT Clinical Trials Network Protocol 0102 is a trial of tandem autologous stem cell transplants versus a single autologous stem cell transplant followed by a matched sibling non-myeloablative allogeneic stem cell transplant in patients up to the age of 70 (with a Karnofsky performance status of ³70). All autologous transplants utilize melphalan 200 mg/m2 while the RIC allogeneic transplant gives only a single fraction of 200  cGy of total body irradiation. GVHD prophylaxis is cyclosporine and mycophenolate mofetil. The primary objective of this study is to compare progression-free survival at 3 years between the two strategies. Approximately 600 subjects have been enrolled on this study, including 150 allografts, which should provide representative data to help define the role of RIC allogeneic transplantation for fit adults up to age 70 years with multiple myeloma. While these studies begin to address the role of RIC transplantation in the younger, older patients with multiple myeloma, the majority of patients with this disease will still be excluded secondary to age (no studies for patients >70 years of age) and the lack of a suitable sibling donor for the majority of patients.

9.  Future Directions Allogeneic transplantation may offer a potentially curative treatment option for selected older adults with hematologic malignancies including multiple myeloma. However, substantial concerns regarding treatment toxicity persist which will continue to limit application of this treatment modality in the true elderly or frail population. Future advances in this field will need to build upon a better understanding of the relationship between physiologic aging and allogeneic transplantation rather than relying on chronologic age cutoffs in research and practice. Future research goals include (1) prospective evaluation of elderly specific transplantation strategies; (2) development of refined patient selection criteria which incorporate comorbidity, physical function, and cognition; and (3) incorporation of additional outcome measures into clinical trials to evaluate transplantation in the context of its impact on quality of life and disability as well as overall survival (Table 9-3).

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Table 9-3.  Future research directions for allogeneic transplantation in older adults. Research goal

Topics for investigation

Development of elderly specific transplantation regimens

Reduced intensity conditioning regimens Optimal donor selection (sibling vs. younger matched unrelated) Optimal GVHD prophylaxis Optimal timing of transplantation

Development and validation of an elderly specific patient selection algorithm

Transplant-specific comorbidity assessment Predictive value of self-report functional status (e.g., Activities of daily living, instrumental activities of daily living) Predictive value of baseline physical performance measures (e.g., walking speed, lower extremity strength/balance) Evaluation of cognitive assessment

Incorporation of additional outcome measures into clinical trials

Quality of life measures Disability assessment

References 1. SEER Cancer Statistics Review 1975–2003. http://seer.cancer.gov/publications/ 2006 2. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A et al (2003) Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 78(1):21–33 3. Blade J, Munoz M, Fontanillas M, San Miguel J, Alcala A, Maldonado J et  al (1996) Treatment of multiple myeloma in elderly people: Long-term results in 178 patients. Age Ageing 25(5):357–361 4. Clavio M, Casciaro S, Gatti AM, Spriano M, Bonanni F, Poggi A et  al (1996) Multiple myeloma in the elderly: Clinical features and response to treatment in 113 patients. Haematologica 81(3):238–244 5. Rodon P, Linassier C, Gauvain JB, Benboubker L, Goupille P, Maigre M et  al (2001) Multiple myeloma in elderly patients: Presenting features and outcome. Eur J Haematol 66(1):11–17 6. Nilsson T, Hoglund M, Lenhoff S, Rylander L, Turesson I, Westin J et al (2003) A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differences. Br J Haematol 120(6):960–969 7. Mileshkin L, Prince HM (2005) The adverse prognostic impact of advanced age in multiple myeloma. Leuk Lymphoma 46(7):951–966 8. Cohen HJ, Bartolucci A (1985) Age and the treatment of multiple myeloma. Southeastern Cancer Study Group experience. Am J Med 79(3):316–324 9. Jantunen E, Kuittinen T, Penttila K, Lehtonen P, Mahlamaki E, Nousiainen T (2006) High-dose melphalan (200  mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (>or  =  65 years) myeloma patients: Comparison with younger patients treated on the same protocol. Bone Marrow Transplant 37(10):917–922 10. Palva IP, Ahrenberg P, Ala-Harja K, Almqvist A, Hanninen A, Ilvonen M et  al (1989) Treatment of multiple myeloma in old patients. Finnish Leukaemia Group. Eur J Haematol 43(4):328–331 11. Wisloff F, Andersen P, Andersson TR, Brandt E, Eika C, Fjaestad K et al (1991) Has the incidence of multiple myeloma in old age been underestimated? The myeloma project of health region I in Norway. Eur J Haematol 47(5):333–337

Chapter 9  The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults  12. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD et  al (2006) Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: Final results of phase III US Intergroup Trial S9321. J Clin Oncol 24(6):929–936 13. Frassoni F, Labopin M, Gluckman E, Prentice HG, Vernant JP, Zwaan F et  al (1996) Results of allogeneic bone marrow transplantation for acute leukemia have improved in Europe with time – a report of the acute leukemia working party of the European group for blood and marrow transplantation (EBMT). Bone Marrow Transplant 17(1):13–18 14. Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E et al (1988) Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med 108(6):806–814 15. Thomas ED, Clift RA, Fefer A, Appelbaum FR, Beatty P, Bensinger WI et  al (1986) Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 104(2):155–163 16. Clift RA, Appelbaum FR, Thomas ED (1993) Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82(7):1954–1956 17. de la Camara R, Alonso A, Steegmann JL, Arranz R, Granados E, RodriguezMacias G et  al (2002) Allogeneic hematopoietic stem cell transplantation in patients 50 years of age and older. Haematologica 87(9):965–972 18. Deeg HJ, Shulman HM, Anderson JE, Bryant EM, Gooley TA, Slattery JT et  al (2000) Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95(4):1188–1194 19. Ditschkowski M, Elmaagacli AH, Trenschel R, Steckel NK, Koldehoff M, Beelen DW (2006) Myeloablative allogeneic hematopoietic stem cell transplantation in elderly patients. Clin Transplant 20(1):127–131 20. Du W, Dansey R, Abella EM, Baynes R, Peters WP, Klein J et al (1998) Successful allogeneic bone marrow transplantation in selected patients over 50 years of age – a single institution’s experience. Bone Marrow Transplant 21(10):1043–1047 21. Farag SS, Elder PJ, Marcucci G, Penza S, Mrozek E, Molina A et  al (2003) Radiation-free regimens result in similar outcomes of allogeneic hematopoietic progenitor cell transplantation in patients aged >or  =  50 years compared to younger adults with low-risk disease. Bone Marrow Transplant 31(2):87–93 22. Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA et  al (1998) Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338(14):962–968 23. Klingemann HG, Storb R, Fefer A, Deeg HJ, Appelbaum FR, Buckner CD et  al (1986) Bone marrow transplantation in patients aged 45 years and older. Blood 67(3):770–776 24. Wallen H, Gooley TA, Deeg HJ, Pagel JM, Press OW, Appelbaum FR et al (2005) Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 23(15):3439–3446 25. Ringden O, Horowitz MM, Gale RP, Biggs JC, Gajewski J, Rimm AA et al (1993) Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA 270(1):57–60 26. Yanada M, Emi N, Naoe T, Sakamaki H, Iseki T, Hirabayashi N et  al (2004) Allogeneic myeloablative transplantation for patients aged 50 years and over. Bone Marrow Transplant 34(1):29–35 27. Gale RP, Bortin MM, van Bekkum DW, Biggs JC, Dicke KA, Gluckman E et  al (1987) Risk factors for acute graft-versus-host disease. Br J Haematol 67(4):397–406 28. Weisdorf D, Hakke R, Blazar B, Miller W, McGlave P, Ramsay N et al (1991) Risk factors for acute graft-versus-host disease in histocompatible donor bone marrow transplantation. Transplantation 51(6):1197–1203 29. Nash RA, Pepe MS, Storb R, Longton G, Pettinger M, Anasetti C et  al (1992) Acute graft-versus-host disease: Analysis of risk factors after allogeneic marrow

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H.D. Klepin and D.D. Hurd transplantation and prophylaxis with cyclosporine and methotrexate. Blood 80(7):1838–1845 30. Atkinson K, Horowitz MM, Gale RP, van Bekkum DW, Gluckman E, Good RA et al (1990) Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood 75(12):2459–2464 31. Carlens S, Ringden O, Remberger M, Lonnqvist B, Hagglund H, Klaesson S et al (1998) Risk factors for chronic graft-versus-host disease after bone marrow transplantation: A retrospective single centre analysis. Bone Marrow Transplant 22(8):755–761 32. Ochs LA, Miller WJ, Filipovich AH, Haake RJ, McGlave PB, Blazar BR et  al (1994) Predictive factors for chronic graft-versus-host disease after histocompatible sibling donor bone marrow transplantation. Bone Marrow Transplant 13(4):455–460 33. Aschan J, Ringden O (1994) Prognostic factors for long-term survival in leukemic marrow recipients with special emphasis on age and prophylaxis for graft-versushost disease. Clin Transplant 8(3 Pt 1):258–270 34. Doney K, Fisher LD, Appelbaum FR, Buckner CD, Storb R, Singer J et al (1991) Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation. Multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival. Bone Marrow Transplant 7(6):453–459 35. Mehta J, Gordon LI, Tallman MS, Winter JN, Evens AM, Frankfurt O et al (2006) Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially? Bone Marrow Transplant 38(2):95–100 36. Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH et al (2001) Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: The effect of donor age. Blood 98(7):2043–2051 37. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al (2007) High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 110(13):4576–4583 38. Popplewell LL, Forman SJ (2002) Is there an upper age limit for bone marrow transplantation? Bone Marrow Transplant 29(4):277–284 39. Shapira MY, Tsirigotis P, Resnick IB, Or R, Abdul-Hai A, Slavin S (2007) Allogeneic hematopoietic stem cell transplantation in the elderly. Crit Rev Oncol Hematol 64(1):49–63 40. Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ et  al (2005) Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 105(4):1810–1814 41. Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ et al (2005) Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: A retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia 19(12):2304–2312 42. Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M et al (2004) Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 10(3):178–185 43. Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG et  al (2004) Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood 104(5):1550–1558 44. Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J et  al (2006) Retrospective comparison of reduced-intensity conditioning and conventional

Chapter 9  The Role of Allogeneic Transplantation for Multiple Myeloma in Older Adults  high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 108(3):836–846 45. Massenkeil G, Nagy M, Neuburger S, Tamm I, Lutz C, le Coutre P et  al (2005) Survival after reduced-intensity conditioning is not inferior to standard high-dose conditioning before allogeneic haematopoietic cell transplantation in acute leukaemias. Bone Marrow Transplant 36(8):683–689 46. Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM et al (2003) Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 102(2):756–762 47. Perez-Simon JA, Diez-Campelo M, Martino R, Brunet S, Urbano A, Caballero MD et al (2005) Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation. Br J Haematol 130(3):394–403 48. Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A et al (2006) Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: The role of dose intensity. Leukemia 20(2):322–328 49. Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C et al (2004) Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: Influence of pretransplantation comorbidities. Blood 104(4):961–968 50. Valcarcel D, Martino R, Sureda A, Canals C, Altes A, Briones J et  al (2005) Conventional versus reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematological malignancies. Eur J Haematol 74(2):144–151 51. Bertz H, Potthoff K, Finke J (2003) Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol 21(8):1480–1484 52. Falda M, Busca A, Baldi I, Mordini N, Bruno B, Allione B et  al (2007) Nonmyeloablative allogeneic stem cell transplantation in elderly patients with hematological malignancies: Results from the GITMO (Gruppo Italiano Trapianto Midollo Osseo) multicenter prospective clinical trial. Am J Hematol 82(10):863–866 53. Kroger N, Shimoni A, Zabelina T, Schieder H, Panse J, Ayuk F et  al (2006) Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS). Bone Marrow Transplant 37(4):339–344 54. Tsirigotis P, Bitan RO, Resnick IB, Samuel S, Ackerstein A, Eladi S et al (2006) A non-myeloablative conditioning regimen in allogeneic stem cell transplantation from related and unrelated donors in elderly patients. Haematologica 91(6):852–855 55. Corradini P, Zallio F, Mariotti J, Farina L, Bregni M, Valagussa P et  al (2005) Effect of age and previous autologous transplantation on nonrelapse mortality and survival in patients treated with reduced-intensity conditioning and allografting for advanced hematologic malignancies. J Clin Oncol 23(27):6690–6698 56. Gomez-Nunez M, Martino R, Caballero MD, Perez-Simon JA, Canals C, Mateos MV et al (2004) Elderly age and prior autologous transplantation have a deleterious effect on survival following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: Results from the Spanish multicenter prospective trial. Bone Marrow Transplant 33(5):477–482 57. Alamo J, Shahjahan M, Lazarus HM, de Lima M, Giralt SA (2005) Comorbidity indices in hematopoietic stem cell transplantation: A new report card. Bone Marrow Transplant 36(6):475–479 58. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al (2005) Hematopoietic cell transplantation (HCT)-specific comorbidity index: A new tool for risk assessment before allogeneic HCT. Blood 106(8):2912–2919

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H.D. Klepin and D.D. Hurd 59. Sorror ML, Sandmaier BM, Storer BE, Maris MB, Baron F, Maloney DG et  al (2007) Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25(27):4246–4254 60. Artz AS, Pollyea DA, Kocherginsky M, Stock W, Rich E, Odenike O et al (2006) Performance status and comorbidity predict transplant-related mortality after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 12(9):954–964 61. Inouye SK, Peduzzi PN, Robison JT, Hughes JS, Horwitz RI, Concato J (1998) Importance of functional measures in predicting mortality among older hospitalized patients. JAMA 279(15):1187–1193 62. Extermann M, Overcash J, Lyman GH, Parr J, Balducci L (1998) Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 16(4):1582–1587 63. Katz S (1983) Assessing self-maintenance: Activities of daily living, mobility, and instrumental activities of daily living. J Am Geriatr Soc 31(12):721–727 64. Lawton MP, Brody EM (1969) Assessment of older people: Self-maintaining and instrumental activities of daily living. Gerontologist 9(3):179–186 65. Repetto L, Fratino L, Audisio RA, Venturino A, Gianni W, Vercelli M et al (2002) Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: An Italian Group for Geriatric Oncology Study. J Clin Oncol 20(2):494–502 66. Cesari M, Kritchevsky SB, Penninx BW, Nicklas BJ, Simonsick EM, Newman AB et al (2005) Prognostic value of usual gait speed in well-functioning older people – results from the Health, Aging and Body Composition Study. J Am Geriatr Soc 53(10):1675–1680 67. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB (1995) Lowerextremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med 332(9):556–561 68. Studenski S, Perera S, Wallace D, Chandler JM, Duncan PW, Rooney E et  al (2003) Physical performance measures in the clinical setting. J Am Geriatr Soc 51(3):314–322 69. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al (2007) A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356(11):1110–1120

Chapter 10 Single Versus Tandem Autologous Hematopoietic Stem Cell Transplant in Multiple Myeloma David H. Vesole

1.  Single Autologous Transplantation It has been known for over 20 years, that high-dose therapy with melphalan can produce a profound anti-myeloma effect. Initially introduced to help overcome the native resistance of myeloma cells to conventional chemotherapy, highdose therapy requiring autologous hematopoietic stem cell support was first evaluated in patients with refractory disease [1]. This resulted in improved response rates and overall survival (OS). This approach was then extended to newly diagnosed patients. In 1996, the seminal randomized study on symptomatic stage II and III patients by the French Myeloma Intergroup, showed conclusively that high-dose therapy yielded a superior disease-free and OS outcome compared to conventional therapy [2]. The 5-year projected survival for the transplant group was 52 versus 12% for the standard therapy (SDT) group (Table 10-1). Whereas, complete responses were observed in only 5% of the conventional therapy group, 22% of the high-dose therapy group achieved complete remissions (CR). The transplant-related mortality was only 2.7% in the setting of bone marrow transplant without hematopoietic stem cell growth factors. Other randomized and nonrandomized comparisons have also demonstrated that high-dose therapy is superior to conventional chemotherapy [3–5]; this included a second large randomized trial by the Medical Research Council Myeloma VII trial also showing an improvement in median eventfree survival (EFS) and OS of approximately 12 months [3]. In an Arkansas study comparing tandem hematopoietic stem cell transplantation (HSCT) to conventional VAD chemotherapy, patients achieving complete response had a median disease-free survival of 50 months and median OS of more than 7 years [4]. Based on these results, multiple myeloma is currently the most common indication for HSCT in North America, with over 5,000 transplants performed yearly (Center for International Blood and Marrow Transplant Research [CIBMTR] estimates). Indeed, national and international guidelines consider upfront HSCT in transplant eligible patients as one of the standard treatment options for newly diagnosed myeloma (http://www.nccn.org).

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_10, © Springer Science + Business Media, LLC 2003, 2010

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Table 10-1.  Randomized trials of conventional chemotherapy compared to single ASCT as upfront therapy. Author

Group

N

Age years

CR% SDT vs. HSCT

p

Criteria for defining CR

OS benefit for HSCT

Comments

Attal et al. [2]

IFM90

200

£65

  5 vs. 22

S

Electrophoresis

Significant benefit

BMT. No GF. TRM 2.7%

Child et al. [3]

MRC7

401

£64

  8 vs. 44

S

EBMT– IBMTR (IF)

Significant benefit

TRM 3%

Blade et al. [6]

PETHEMA

216

£65

11 vs. 30

S

EBMT– IBMTR (IF)

No OS/EFS benefit

Only PR and CR included

Barlogie et al. [7]

USIG

899

<70

15 vs. 17

NS

EBMT– IBMTR (IF)

No OS benefit

34% delayed HSCT

SDT standard dose therapy, HSCT hematopoietic stem cell transplant, S statistically significant, NS not significant, IF immunofixation, BMT bone marrow transplant, GF growth factors, TRM transplant-related mortality

Furthermore, high-dose therapy with autologous transplantation and improved supportive care measures has resulted in improvement in myeloma survival rates over the past three decades [5]. In contrast, there are also randomized clinical trials that failed to show an improvement in event-free survival or OS. The Spanish PETHEMA trial included one hundred sixty-four patients who were randomly assigned: 83 to continued conventional chemotherapy and 81 to HSCT [7]. The CR rate was significantly higher with HSCT (30 vs. 11%; p  =  0.002). However, progressionfree survival (PFS) was not significantly different between HSCT and conventional therapy (median, 42 vs. 33 months; p  =  not significant), and OS was similar in both groups (median, 61 vs. 66 months). Survival after relapse was identical in the two arms (15.9 vs. 16.4 months). A large United States Intergroup trial (S9321) included 899 patients: with a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HSCT, n  =  261 patients; SDT, n  =  255 patients) [8]. Similarly, PFS and OS durations did not differ between the HSCT and SDT arms, with 7-year estimates of PFS of 17 and 16%, respectively, and OS of 37 and 42%, respectively.

2.  Differences in the Single HSCT Studies The United States Intergroup study and the Spanish PETHEMA study are not straightforward comparisons of conventional chemotherapy versus HSCT. In the PETHEMA trial only patients achieving PR or CR to initial chemotherapy were randamized to HSCT versus Continuing Conventional Chemotherapy [7]. Patients who were refractory to initial conventional chemotherapy were thus excluded. This suggests that the study was unable to demonstrate an increase in the EFS or OS between conventional chemotherapy and HSCT in patients responding to initial chemotherapy (34 vs. 42 months and 67 vs. 65 months for EFS and OS between conventional therapy and HSCT). Although there was no difference in EFS or OS, this study did demonstrate a higher CR rate in the HSCT arm. The findings of this study caution against accepting CR as a surrogate for event-free survival benefit in HSCT for MM. Also, these findings suggest that there may only be a small additional benefit to HSCT in patients who achieve CR to induction therapy.

Chapter 10  Single Versus Tandem Autologous Hematopoietic Stem Cell 

The United States Intergroup Study, S9321, is the largest of the studies comparing conventional chemotherapy to high-dose therapy [8]. All patients received 3–4 cycles of VAD chemotherapy followed by high-dose cyclophosphamide for stem cell mobilization. The patients were randomized to receive melphalan 140 mg/m2 with total body irradiation 1,200 cGy or VBMCP for 1 year. Thus, the study compared “maintenance” VBMCP chemotherapy versus HDT with HSCT for EFS. Responding patients in each arm underwent a second randomization to either observation or interferon maintenance. At the time of relapse in the VBMCP arm, patients were encouraged to undergo HSCT. Although not part of the original design, this was incorporated into the treatment later to compare early versus late transplant. The VBMCP and early HSCT groups were similar in terms of CR, EFS (21 vs. 25 months, p = 0.14) and OS (53 vs. 62 months, p = 0.87). Interpretation of the results for OS was murkier since 52% of patients in the VBMCP arm had a late transplant at relapse/progression. Interestingly, the CR rates were also not significantly different between conventional chemotherapy versus HDT (15 vs. 17%) possibly implying that the transplant regimen of melphalan 140 mg/m2 with TBI 1200 cGy may be an inferior regimen compared to melphalan 200 mg/m2 used in the Arkansas studies. Melphalan 140  mg/m2 plus TBI 800  cGy has been shown to have similar EFS but inferior OS (p = 0.05) compared to melphalan 200  mg/m2 in the randomized French study IFM95-02 [9] and an Arkansas retrospective study [10]. Finally, a recent meta-analysis of 9 randomized clinical trials with a minimum of 2 years of follow-up which included 2,411 patients demonstrated a superior PFS benefit (Fig.  10-1) but not OS benefit (Fig. 10-2) for HSCT [11]. There was an increase in treatment-related mortality in the transplant group. It should be noted that some of these trials

Fig. 10-1.  PFS benefit of upfront HDT/transplant vs. SDT

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Fig. 10-2.  Lack of OS benefit with upfront HDT/transplant vs. SDT

were completed in the early 1990s before the routine use of peripheral blood stem cells and hematopoietic growth factors, factors that may have impacted on transplant-related mortality. One question that commonly arises: should newly diagnosed patients be treated until they achieve a partial remission before proceeding to transplant? In patients who are initial responders to treatment (as noted in the PETHEMA study), HSCT may not add survival benefit over continuing conventional therapy. In initial nonresponders with minimally responsive or primarily refractory disease, HSCT remains the most effective means of achieving a response. Alexanian et  al. observed that patients with primary resistant disease who received intensification within 1 year achieved a high frequency of response (69%), a 16% CR rate, and a survival benefit [12]. HSCT beyond 1 year was less effective affirming the greater value of early intensive therapy for these patients. In the Royal Marsden experience 40% of nonresponders to initial CVAMP therapy achieved CR with melphalan 200 mg/m2 [13]. In the Mayo Clinic experience 20% patients in the primary refractory group achieved CRs following high-dose therapy compared to 35% in the chemosensitive group yet the groups had a similar PFS [14]. Therefore, the absence of response to initial induction does not preclude a good response to HSCT. A recent preliminary report by the PETHEMA group evaluated patients with primary refractory disease: those with stable disease (n = 50) versus those with progressive disease (n = 31) to induction therapy [15]. Both groups were compared to patients with chemotherapy-sensitive disease. They found comparable OS in patients with chemotherapy-sensitive disease and in patients with stable disease. Patients with progressive disease to induction therapy had a very poor prognosis.

Chapter 10  Single Versus Tandem Autologous Hematopoietic Stem Cell 

3.  Timing of Transplant Another issue that has been raised is the optimal timing of the transplant. Two randomized studies comparing early versus late transplant at relapse showed comparable OS [8, 16]. In the French study, they reported higher quality of life scores in the upfront transplant cohort suggesting a valid benefit for upfront HSCT [16]. Therefore, high-dose therapy with autologous stem cell transplantation has been well established as appropriate care for front-line therapy in many newly diagnosed multiple myeloma patients, particularly those younger than 70 years of age. 3.1.  Tandem Autologous Transplantation Sequential planned tandem HSCT was developed in an attempt to increase dose intensity and achieve deeper sustained remissions. Reported CR rates with single HSCT have been in the 25–35% range, whereas tandem autologous transplantation has an expected CR rate ranging from 35% to 50%. After the feasibility of double intensification with HSCT had been reported [17–19], the Arkansas group pioneered the tandem planned autologous transplant approach in their Total Therapy I program with noncross resistant induction chemotherapy regimens culminating in tandem autologous transplantation [20]. They observed impressive EFS and OS of 43 and 68 months, respectively, which were superior to historical controls. In a recent update of the original cohort of 231 patients, 33% of the patients were alive at 10 years and 17% at 15 years with 15 and 7%, respectively, in continuous remission [21]. The results of the Arkansas Total Therapy II trial which incorporates thalidomide into a tandem transplant approach have been reported [22]. They observed superior 5-year continuous CR (60%) and improved EFS (50% at 5 years) compared to Total Therapy I. The median follow-up of 2.5 years is not yet mature enough to compare the OS. The current Arkansas approach – Total Therapy III – includes bortezomib in the induction regimen and post-transplant consolidation [23] with further improvement in the depth and duration of responses. At 24 months, 83% had achieved near-complete remission, which was sustained in 88% at 2 years from its onset. With a median follow-up of 20 months, 2-year estimates of event-free survival and OS were 84 and 86%, respectively. Based upon the early results of Total Therapy I, the French Myeloma Intergroup initiated a randomized trial (IFM 94) comparing single and double HSCT [24]. Three hundred and ninety-nine previously untreated MM patients were randomly assigned to receive either a single HSCT using (Mel 140 mg/ m2 + TBI 8  Gy) or a double HSCT (Mel 140  mg/m2 followed by Mel 140  mg/m2 + TBI 8  Gy). Patients then received interferon-2a maintenance therapy. The projected 7-year EFS and OS benefits were significant for the double HSCT arm (10 vs. 20% for EFS and 21 vs. 42% for OS, respectively). Of note, in a subgroup analysis, the patients most likely to benefit from the second transplant were those who achieved less than very good PR (defined as >90% reduction in paraprotein) to the first transplant. Additional randomized clinical trials from Italy (Bologna 96), Netherlands (HOVON 24), Germany (GMMG-HD2), and France (MAG 95) have compared double intensive therapy to single intensive therapy (Table  10-2) [25–28].

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Table 10-2.  Randomized trials of single vs. double autologous ASCT. Age Conditioning regimen CR% single EFS% single OS% single limit first → second vs. double vs. double vs. double

Author

N

IFM 94 [23]

399 60

Mel140 + TBI → Mel 140 42 vs. 50

25 vs. 30*

48 vs. 58*

Follow-up 75M

HOVON 24 [25]

304 65

56M

Mel 140 → Cy 120 + TBI 13 vs. 32*

21 vs. 22*

55 vs. 50

GMMG HD2 [26] 261 65

Mel 200 → Mel 200

23 vs. 29*

No difference NR

MAG 95 [27]

227 55

Mel140 + CCNU/VP16/ 39 vs. 37 CY-TBI vs. MEL 140 → Mel 140 + TBI

31 vs. 33

49 vs. 73**

53M

Bologna 96 [24]

228 60

Mel 200 → Mel 120 + BU 12

35 vs. 48

22 vs. 35*

59 vs. 73

55M

Tunisia [28]

195 60

Mel 200 → Mel 200 vs. Mel 200 → *thal 100×6 mo

68 vs. 54*

85 vs. 57*

85 vs. 65*

33M

NR

*Statistically significant difference (p < 0.05) **OS difference statistically superior for non-CD34 selected tandem transplants only in subset analysis Mel melphalan (doses in mg/m2), CY cyclophosphamide, TBI total body irradiation, BU busulfan, NR not reported

The preliminary data show an EFS benefit for the tandem approach in three out of the four studies. OS benefit has thus far been shown only for the IFM 94 study. Even the MAG study, which had previously failed to show any meaningful outcome differences between the tandem and single transplant arms, has been re-analyzed recently [28]. In the subgroup of patients who received non-CD34+ selected stem cell products, there was a significant OS advantage to the tandem arm (30 vs. 40% at 7 years, p = 0.04) although the EFS was still similar. Recently, the Tunisian myeloma group reported a Phase III trial of tandem autologous transplant (without any maintenance) with a single transplant with thalidomide maintenance (100 mg) for 6 months post-HSCT [29]. At the time of progressive disease, the single HSCT arm would proceed to a second HSCT. A total of 202 newly diagnosed patients under age 60 were enrolled on the trial. They received thalidomide plus dexamethasone for induction therapy. The transplant regimen was melphalan 200 mg/m2. Thalidomide 100 mg daily was started 3 months post-transplant for 6 month duration. A second transplant was planned at the time of disease progression. In the tandem transplant arm, the patients were to receive thalidomide 200 mg daily at the time of disease progression. Over 80% received the assigned treatment in each arm. After second HSCT and 6 months of maintenance thalidomide, the CR + VGPR were 54 and 68%, respectively (p = 0.04). With a median follow-up of 33 months, 3-year PFS, and OS were 57 versus 85% (p = 0.02) and 65 versus 85% (p = 0.04), respectively. Prognostic factors showed that the benefit of the thalidomide maintenance was observed only in patients who did not achieve at least a VGPR after HSCT. Of note, however, is that the tandem transplant arm did not receive thalidomide. Also, only 18 of the patients received thalidomide as salvage therapy. Thus, the OS improvement is difficult to interpret since less than 50% of the patients received the thalidomide as salvage therapy. Further, only nine patients received a salvage second transplant. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has recently completed a large Phase III clinical trial comparing tandem

Chapter 10  Single Versus Tandem Autologous Hematopoietic Stem Cell 

autologous HSCT to autologous transplant followed by a matched sibling nonmyeloablative allogeneic transplant. The proposed successor trial to this study will be a three arm study comparing single transplant with lenalidomide maintenance to a single transplant with bortezomib, lenalidomide, dexamethasone consolidation followed by lenalidomide maintenance to tandem autologous transplant with lenalidomide maintenance therapy. Table  10-2 is a summary of the randomized data in tandem autologous transplant.

4.  Benefits of Tandem Transplantation It was noted in the IFM 94 trial that the OS for patients undergoing tandem transplants diverged significantly from the single transplant arm only after the first 4 years of follow-up [24]. Furthermore, the results of this study show no significant increase in CR with the second transplant on an intentto-treat basis, although patients who actually HAD the second transplant did have higher CR rates compared to patients who only had a single transplant (63 vs. 49%, respectively). The authors suggest that this indicates that the difference in projected survival with double transplants does not correlate with improved response rates but longer duration of responses. This could also explain why differences in survival are not apparent with shorter follow-up in the other randomized studies of tandem transplantation. Also, the IFM results appear inferior to the Arkansas tandem transplant data in terms of crude rates of CR, EFS, and OS. These differences may be related to differences in patient selection, induction, and most likely the transplant conditioning therapy: the IFM 94 utilized Mel 140  mg/m2 followed by Mel 140 mg/m2 + TBI 8 Gy (total melphalan dose of 280 mg/m2) while the Arkansas regimen was Mel 200  mg/m2 followed by Mel 200  mg/m2 (total melphalan dose of 400 mg/m2). The patients who achieve the maximum benefit from the second planned HSCT are those who do not achieve a CR or a very good PR within 3 months after the first HSCT. In the IFM 94 trial, the probability of 7-year survival was 11% with single transplant versus 43% with the tandem approach [24]. The Bologna 96 data [25] also demonstrate that tandem HSCT was of particular benefit to patients who failed to respond to first-line therapy and/or were not in CR or near CR following the first transplant. Based on the IFM 94 and Bologna 96 evidence, a patient who fails to achieve a good PR after the first HSCT should be offered a tandem second transplant within 3–6 months of the first HSCT. Routine tandem transplants should otherwise only be considered in the context of well-designed clinical trials and not the standard of care at this time. The lack of OS benefit in any randomized study other than IFM 94 is striking. As discussed above, the explanations may include the differences in conditioning regimens, the failure to improve CR rates with second transplants, the lack of sufficiently lengthy follow-up, and the improving salvage options available to patients who relapse. Short follow-up and improvements in salvage therapy including late second transplants almost certainly account for the observed EFS benefits without an OS advantage for the tandem procedure.

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D.H. Vesole

5.  Second Transplants as Salvage Therapy The timing of a second HSCT in patients who have undergone a prior HDT with HSCT is an unanswered question. While the IFM 94 and Bologna 96 results suggest that for patients who do not achieve a good partial remission or near CR within 3 months after the first transplant, an immediate second transplant may be optimal, there are reports of the efficacy of salvage second transplants at relapse (31–35). Tricot et al. have shown that a salvage HSCT at relapse after prior auto transplant showed benefit for patients with >12 months remission duration and normal beta-2 microglobulin [30]. Unfortunately, there are no randomized studies that compare a salvage second transplant at relapse to a planned upfront tandem second transplant. The European Bone Marrow Transplant Registry (EBMT) published a registry-based analysis suggesting the performance of a second planned autologous transplant before relapse and within 6–12 months of the first transplant resulted in superior outcomes [36]. The Arkansas group performed serial landmark analyses to define the optimal timing of a planned second transplant in their original total therapy patient population [20]. EFS and OS both were longer among the patients who had received a second transplant within 13 months (85% of second transplants had been completed at that time) compared with the others receiving their second cycle of high-dose therapy later or not at all. A later analysis with a larger (1,000 patients) group undergoing melphalan-based tandem transplants suggested that timely application of a second transplant was significant for EFS and OS [37].

6.  Maintenance Therapy Following Transplant Interferon, a mainstay for maintenance therapy after transplantation, has been shown to be ineffective in the United States Intergroup S9321 trial [8]. Although corticosteroids have been shown to improve EFS following conventional therapy, there has not been a clinical trial to evaluate their efficacy post-HSCT [38, 39]. Other maintenance strategies are outlined in Table 10-3 [45–51]. Thalidomide, an effective agent in MM for relapsed disease and as induction therapy, has been evaluated as maintenance therapy post-transplant. Three randomized studies have demonstrated the benefit of thalidomide, either as a single agent or in combination, as maintenance therapy after autologous transplantation [22, 40, 41]. In a French trial, thalidomide maintenance improved the 3-year EFS compared to observation (52 vs. 36%) and 4-year OS (87 vs. 77%) [40]. Of note, only those patients who did not achieve at least a very good partial remission were the patients who benefited from thalidomide maintenance. Similar findings were observed in the Tunisian study [29]. An Arkansas trial showed superior CR rates (62 vs. 43%) and 5-year EFS with thalidomide (56 vs. 44%) but no improvement in OS [22]. The preliminary report by the Australian ALLG MM6 study of thalidomide plus prednisone for 12 months versus observations post-HSCT also showed an improvement in PFS (90 vs. 69%, p = 0.005) and OS (91 vs. 80%, p = 0.21) although this was observed until beyond the first year from transplant [41]. Recently, BMT CTN completed a large trial of over 500 autologous transplant recipients randomized to either thalidomide plus dexamethasone (for 1 year) or observation post-tandem HSCT. The results of these trials

Chapter 10  Single Versus Tandem Autologous Hematopoietic Stem Cell 

151

Table 10-3.  Maintenance after primary myeloma therapy. Study

N

Maintenance

PFS (months)

OS

US Intergroup Trial S9321 [7]

249

IFN

25 vs. 21 (p = 0.05)

58 vs. 53 (p = 0.8)

Cunningham [45]

  84

IFN

NSa

NSa

EBMT [46]

892

IFN

29 vs. 20 (p = 0.006)

78 vs. 47 (p = 0.007)

HOVON-50b [47]

128

IFN

13.5 vs. 8.5 (p = 0.04)

41 vs. 38.4 NSa

SWOGb [48]

125

Pred

14 vs. 5 (0.03)

37 vs. 26 (p = 0.05)

NCIC MY7b [49]

307

Dex

33 vs. 23

46.3 vs. 43.8

Arkansas TT2 vs. TT1 [50]

668 (TT2) 231 (TT1)

IFN

50 vs. 25 (p < 0.001)

70 vs. 60 (p = 0.06)

NCIC MY9 [51]

  67

Thal + Pred

42.2

91% at 1 year

IFM 99 02 [52]

588

Thal + Pam

56

EFS p < 0.009)

Pam

37

OS p < 0.04

Obs

34

a

Outcomes at 77 months Studies that include maintenance after a primary treatment other than transplant PFS progression-free survival, OS overall survival, IFN interferon-a, OR odds ratio, NS not statistically significant, Pred prednisone, Dex dexamethasone, TT1/TT2 total therapies one and two, Thal thalidomide, Pam pamidronate; NR not reported b

Table 10-4.  Post-transplant maintenance options and recommendations. Pro

Cons

Currently open trials

Agent/regimens

Dose

Dexamethasone

40 mg 4 d/mo Prolong PFS after SDT

Steroid side effects –

Thalidomide

50–100 mg

Prolong PFS/OS (IFM 99-02)

Neuropathy, DVT

Revlimid

10 mg

No available results

DVT, CALGB/ECOG myelosupression 100104

  Thal + Prednisone

200/50

  Thal + Dexamethasone

200/40

Good tolerability, Risk for compound ECOG/NCIC 76% of patients on side effects MY10 maintenance after 18   BMT CTN #0102 months (NCIC MY9)

Recommendations

(1) Clinical trial preferred whenever possible

HOVON/ GMMG-HD3

Combinations

(2) Thalidomide 50–100 mg daily and dexamethasone 40 mg × 4 days each month if the patient has not been treated with this regimen or responded to this regimen as induction therapy (3) Lenalidomide 10 mg days 1–21 or 1–28. Duration of treatment is still unknown, however most studies include 1–2 years post-transplant or until relapse or disease progression

are not anticipated until at least 2009. The Cancer and Leukemia Group B (CALGB) in collaboration with the Eastern Cooperative Oncology Group and the BMT CTN is currently accruing patients to single agent lenalidomide versus observation following a single HSCT. Upon completion of the CALGB trial, the proposed BMT CTN post-HSCT lenalidomide maintenance trial will be activated. Table  10-4 shows recently completed or currently active maintenance trials. Trials utilizing bortezomib maintenance therapy posttransplant will be initiated in the near future.

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7.  Novel Pre-transplant Regimens Until the recent introduction of novel agents, immunomodulatory drugs, and proteosome inhibitors, into our treatment paradigm for multiple myeloma, high-dose therapy with autologous HSCT provided the best opportunity for most patients to achieve a complete response and to prolong EFS. Novel anti-myeloma combinations are now revolutionizing the induction treatment and raising new questions in transplantation for MM. The most recently approved novel agents thalidomide, bortezomib, and lenalidomide in combination with dexamethasone have transformed the therapeutic options available to patients with relapsed MM and are now being integrated into induction treatment [42–44, 53–63]. Initial studies have been extremely promising with response rates close to 90% and with complete response rates close to 25% (Table 10-5). When these agents are combined with additional agents, the depth of response has improved further as shown in the Arkansas Total Therapy II and III trials (Fig. 3) [22, 23]. It must be noted, however, that the durability of responses induced by novel agent combinations is at this point unknown. If the sustainability of these responses is proven with longer follow-up, it is likely that such induction combinations might displace or delay high-dose treatment.

Table 10-5.  Impact of novel induction strategies on CR rates. Author

Regimen

Overall response rates (%)

CR or nCR + CR rates (%)

N

Palumbo [53]

MPT

76

28

255

Cavenagh [54]

PAD

95

29

  21

Harousseau [55]

VD

73

17

  18

Jagannath [56]

VD or V

88

25

  32

Wang [57]

VDT

92

19

  36

Richardson [58]

V

30

11

  46

Facon [59]

MPT

84

14

  95

Mateos [60]

VMP

85

28

  60

Barlogie [22]

VDT-PACE  +  tandem ASCT

Over 90

83% post-ASCT

303

Rajkumar [42]

Lenalidomide-D

91

38

  34

Rajkumar [41]

Thalidomide-D

63

CR

103

Palumbo [61]

Lenalidomide-MP

67

11

  24

Goldschmidt [62]

TAD followed by ASCT

80

7

406

Rosinol [63]

V alt D

65

12

  40

Caveat: The overall impact of these novel regimens on survival, long-term transplant outcomes, and post-transplant complications are not yet defined since these are pilot data PAD Bortezomib/Doxorubicin/Dexamethasone, MPT MEL/Prednisone/Thalidomide, VDT Bortezomib/Dexamethasone/ Thalidomide, VD Boretzomib/Dexamethasone, V alt D–alternating cycles, V–Bortezomib, TAD Thalidomide/ Adriamycin/Dexamethasone, VDT-PACE Bortezomib/Dexamethasone/Thalidomide/Cisplatin/Adriamycin/Cytoxan/Etoposide D Dexamethasone

Chapter 10  Single Versus Tandem Autologous Hematopoietic Stem Cell 

8.  Conclusion Randomized clinical trials have firmly established the role of upfront autologous transplantation in newly diagnosed MM. While novel agents in combination might result in comparable CR rates to single HSCT, there are insufficient data to recommend any one of the alternative induction strategies outside of clinical trials. With additional time, the newer agents may either supplant transplantation or change our current algorithm by delaying transplants until disease relapse. There is evidence that delayed transplantation is efficacious. Thus, it is doubtful that transplants will be replaced even by highly active newer therapies. Tandem autologous transplants have consistently shown better EFS compared to single autologous transplants but to date only the IFM 94 has shown an OS advantage. Given the improvement in salvage therapies, EFS not OS should be the primary objective of transplant trials. Therefore, the current recommendations for newly diagnosed MM are the following: collect sufficient autologous stem cells for at least 2 transplants and proceed to tandem autotransplants if the patient does not achieve at least a fairly good partial remission (defined as a decrease in paraprotein by >90% from diagnosis) after the first autologous transplant. This is one of the standards of care at this time. For those patients who do achieve a fairly good partial remission, a second transplant should be considered at the time of disease progression. The long-term benefit of maintenance therapy has not been clearly determined. Ideally, patients should be enrolled on clinical trials to assess this concept. In the absence of a clinical trial, it appears that immunomodulatory drugs provide superior EFS in patients who do not achieve a appreciable partial remission with HSCT. It is reasonable to treat these patients with an immunomodulatory agent. The dose and duration of treatment remains unknown.

References 1. McElwain TJ, Powles RL (1983) High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 2:822–824 2. Attal M, Harousseau JL, Stoppa AM et al (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 335:91–97 3. Child JA, Morgan GJ, Davies FE et al (2003) High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875–1883 4. Barlogie B, Jagannath S, Vesole DH et al (1997) Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 89:789–793 5. Kristinsson SY, Landgren O, Dickman PW et al (2007) Patterns of survival in multiple myeloma: A population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol 25:1993–1999 6. Hari P, Pasquini MC, Vesole DH (2006) New questions about transplantation in multiple myeloma. Oncology 20:1230–1242 7. Blade J, Rosinol L, Sureda A et al (2005) High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: Long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 106:3755–3759 8. Barlogie B, Kyle RA, Anderson KC et al (2006) Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: Final results of phase III US Intergroup Trial S9321. J Clin Oncol 24:929–936

153

154 

D.H. Vesole 9. Moreau P, Facon T, Attal M et al (2002) Comparison of 200 mg/m(2) melphalan and 8  Gy total body irradiation plus 140  mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood 99:731–735 10. Desikan KR, Tricot G, Dhodapkar M et al (2000) Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone. Bone Marrow Transplant 25:483–487 11. Koreth J, Cutler CS, Djulbegovic B et  al (2007) High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 13:183–196 12. Alexanian R, Weber D, Delasalle K, Handy B, Champlin R, Giralt S (2004) Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma. Bone Marrow Transplant 34:229–234 13. Singhal S, Powles R, Sirohi B, Treleavan J, Kulkarni S, Mehta J (2002) Response to induction chemotherapy is not essential to obtain survival benefit from highdose melphalan and autotransplantation in myeloma. Bone Marrow Transplant 30:673–679 14. Kumar S, Lacy MQ, Dispenzieri A et al (2004) High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy. Bone Marrow Transplant 34:485–490 15. Blade J, Rosinol L, Garcia-Sanz R et al (2007) A PETHEMA study of high-dose therapy/stem cell support (HDT), including tandem transplant, in primary refractory multiple myeloma (MM): Identification of two populations with different outcomes. Proc Am Soc Clin Oncol 25(Suppl 18S), abstract 8021 16. Fermand JP, Ravaud P, Chevret S et al (1998) High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 92:3131–3136 17. Bjorkstrand B, Ljungman P, Bird JM, Samson D, Gahrton G (1995) Double highdose chemoradiotherapy with autologous stem cell transplantation can induce molecular remissions in multiple myeloma. Bone Marrow Transplant 15:367–371 18. Harousseau JL, Milpied N, Laporte JP et  al (1992) Double-intensive therapy in high-risk multiple myeloma. Blood 79:2827–2833 19. Jagannath S, Vesole DH, Glenn L, Crowley J, Barlogie B (1992) Low-risk intensive therapy for multiple myeloma with combined autologous bone marrow and blood stem cell support. Blood 80:1666–1672 20. Barlogie B, Jagannath S, Desikan KR et al (1999) Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93:55–65 21. Barlogie B, Tricot G, van Rhee F et al (2006) Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 135:158–164 22. Barlogie B, Tricot G, Anaissie E et al (2006) Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354:1021–1030 23. Barlogie B, Anaissie E, van Rhee F et  al (2007) Incorporating bortezomib into upfront treatment for multiple myeloma: Early results of total therapy 3. Br J Haematol 138:176–185 24. Attal M, Harousseau JL, Facon T et  al (2003) Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495–2502 25. Cavo M, Tosi P, Zamagni E (2007) Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 25:2434–2441

Chapter 10  Single Versus Tandem Autologous Hematopoietic Stem Cell  26. Sonneveld P, van der Holt B, Segeren CM et  al (2007) Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: Longterm follow-up of the Dutch Cooperative Group HOVON 24 trial. Haematologica 92:928–935 27. Goldschmidt H (2005) Single vs. double high-dose therapy in multiple myeloma: Second analysis of the GMMG-HD2 Trial. Haematologica 90(Suppl 1):38 Abstract PL8.02 28. Fermand JP, Alberti C, Marolleau JP (2003) Single versus double high dose therapy supported with autologous blood stem cell transplantation using unselected or CD34 enriched ABSC: Results of a two by two designed randomized trial in 230 young patients with multiple myeloma. Hematol J 4(Suppl 1):S59 29. Abdelkefi A, Ladeb S, Torjman L et al (2007) Single autologous stem cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: Results of a multicenter randomized clinical trial. Blood 111(4):1805–1810 30. Tricot G, Jagannath S, Vesole DH et  al (1995) Relapse of multiple myeloma after autologous transplantation: Survival after salvage therapy. Bone Marrow Transplant 16:7–11 31. Mehta J, Tricot G, Jagannath S et  al (1998) Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft. Bone Marrow Transplant 21:887–892 32. Kulkarni S, Powles R, Singhal S et al (1998) Second autografts for relapsed multiple myeloma: Is tandem autotransplantation better? Clinical care: recurrence, secondary neoplasia and late complications after transplantation. Blood 92(Suppl 1): 344b 33. Elice F, Raimondi R, Tosetto A et  al (2006) Prolonged overall survival with second ondemand autologous transplant in multiple myeloma. Am J Hematol 81:426–431 34. Alvares CL, Davies FE, Horton C et al (2006) The role of second autografts in the management of myeloma at first relapse. Haematologica 91:141–142 35. Qazilbash MH, Saliba R, De Lima M et al (2006) Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 106:1084–1089 36. Morris C, Iacobelli R, Brand B et al (2004) Benefit and timing of second transplantations in multiple myeloma: clinical findings and methodological limitations in a European group for blood and marrow transplantation registry study. J Clin Oncol 22:1674–1681 37. Desikan R, Barlogie B, Sawyer J et  al (2000) Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 95:4008–4010 38. Berenson JR, Crowley JJ, Grogan TM et  al (2002) Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99:3163–3168 39. Shustik C, Belch A, Robinson J et al (2007) A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136:203–211 40. Attal M, Harousseau J, Leyvraz S et  al (2006) Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108:3289–3294 41. Spencer A, Prince M, Roberts A, et al (2006) First Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) Trial of thalidomide and alternate day prednisolone following autologous stem cell transplantation (ASCT) for patients with multiple myeloma (ALLG MM6). Blood 108, abstract 58

155

156 

D.H. Vesole 42. Rajkumar SV, Blood E, Vesole D et al (2006) Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24:431–436 43. Lacy MG, Gertz MA, Dispenzieri A et al (2007) Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc 82:1179–1184 44. Rajkumar SV, Jacobus S, Callander N et  al (2006) A randomized phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group. Blood 108, abstract 799 45. Jagannath S, Durie BG, Wolf J et  al (2005) Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776–783 46. Cunningham D, Powles R, Malpas J et al (1998) A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: longterm follow-up results. Br J Haematol 102:495–502 47. Bjorkstrand B, Svensson H, Goldschmidt H et al (2001) Alpha-interferon maintenance treatment is associated with improved survival after high-dose treatment and autologous stem cell transplantation in patients with multiple myeloma: a retrospective registry study from the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 27:511–515 48. Goldschmidt H, Sonneveld P, Cremer FW et  al (2003) Joint HOVON-50/ GMMG-HD3 randomized trial on the effect of thalidomide as part of a high-dose therapy regimen and as maintenance treatment for newly diagnosed myeloma patients. Ann Hematol 82:654–659 49. Berenson JR, Crowley JJ, Grogan TM et  al (2002) Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99:3163–3168 50. Shustik C, Belch A, Robinson S et al (2007) A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 136:203–211 51. Barlogie B, Tricot G, Rasmussen E et al (2006) Total therapy 2 without thalidomide in comparison with total therapy 1: Role of intensified induction and posttransplantation consolidation therapies. Blood 107:2633–2638 52. Stewart AK, Chen CI, Howson-Jan K et  al (2004) Results of a multicenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant. Clin Cancer Res 10:8170– 8176 53. Palumbo A, Bringhen S, Caravita T et al (2006) Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 367:825–831 54. Oakervee HE, Popat R, Curry N et al (2005) PAD combination therapy (PS-341/ bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129:755–762 55. Harousseau JL, Attal M, Leleu X et  al (2006) Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Results of an IFM phase II study. Haematologica 91:1498–1505 56. Jagannath S, Durie BG, Wolf J et  al (2005) Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776–783

Chapter 10  Single Versus Tandem Autologous Hematopoietic Stem Cell  57. Wang M, Giralt S, Delasalle K et  al (2007) Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology 12:235–239 58. Richardson P, Chanan-Khan A, Schlossman R et  al (2005) A multicenter phase II trial of bortezomib in patients with previously untreated multiple myeloma: Efficacy with manageable toxicity in patients with unexpectedly high rates of baseline peripheral neuropathy. Blood 106:2548 59. Facon T, Mary JY, Hulin C et al (2007) Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): A randomised trial. Lancet 370:1209–1218 60. Mateos MV, Hernandez JM, Hernandez MT et al (2006) Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: Results of a multicenter phase 1/2 study. Blood 108:2165–2172 61. Palumbo A, Falco P, Corradini P (2007) et al Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: A report from the GIMEMA– Italian Multiple Myeloma Network. J Clin Oncol 25:4459–4465 62. Goldschmidt H, Sonneveld P, Breitkreuz I et al (2005) HOVON 50/GMMG-HD3Trial: Phase III study on the effect of thalidomide combined with high dose melphalan in myeloma patients up to 65 years. Blood 106:424 63. Rosinol L, Oriol A, Mateos MV et al (2007) Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics. J Clin Oncol 25:4452–4458

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Chapter 11 Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma Frank Heinzelmann, Hellmut Ottinge, and Claus Belka

1.  Introduction Non-Hodgkin’s lymphomas (NHL), a heterogenous group of malignancies arising from lymphoid tissue, account for almost 5% of all cancers occurring in the United States [1]. With an estimated 63,190 new cases and 18,660 cancer deaths projected in 2007 in the United States, NHL is the fifth most common malignant neoplasm after the breast, prostate, lung, and colon [2]. The incidence and mortality rates were reported to have risen steadily in Western countries over the past decades and have doubled between 1950 and 1989, from 5.9 to 13.7 per 100,000 persons per year [3] but the incidence rate had slowed to 1–2% in the 1990s [4, 5]. Based on a large international study, follicular lymphoma (FL), a mature B-cell neoplasm, represents the second most common subtype of NHL with approximately 25% of cases; diffuse large B cell lymphoma (DLBCL) is more common (~30%) [6]. Rates for FL are two to three times greater among whites than among blacks [7]. FL is most commonly seen in middle-aged individuals and the elderly, with a median age of 59 years. Females (52%) are slightly more often affected than males (48%) [8]. The etiology is uncertain, but immunosuppression, specific autoimmune disorders, infectious agents, and environmental factors contribute [9]. FL is pathologically well characterized. Unlike other malignant lymphomas three different malignancy grades are defined according to the degree of centroblasts [10] with grade 3 being subdivided into grade 3a and 3b [11]. While it is broadly accepted that grade 3b FL behaves clinically more like DLBCL and should be treated accordingly, it remains questionable whether the discrimination of grades 1–3a is of clinical significance.

2.  Prognosis and General Treatment Approaches In general, for FL the aim of therapy is to maintain the best quality of life and to initiate treatment when patients develop symptomatic disease such as bulky lymphadenopathy, splenomegaly, risk of local compressive disease, marrow From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_11, © Springer Science + Business Media, LLC 2003, 2010

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compromise, or rapid disease progression. Any alteration of this approach, the so-called watchful waiting, requires demonstration of improved survival with early application of therapy or identification of criteria that define patients at high risk to initiate early therapy. In this regard, the Follicular Lymphoma International Prognostic Index (FLIPI) defines three prognostic risk groups with age ³60 years, stage III/IV disease, elevated LDH level, hemoglobin <12 g/dl, and a number of nodal sites ³5 as unfavorable factors [12]. For firstline treatment there are many therapies available with no clear consensus for an optimal first-line treatment. In patients with early stages I and II, representing 10–30% of the patients with FL [8], external beam radiotherapy (RT) using doses of 26–50 Gray (Gy) has a curative potential and is applied as involved/extended field or total lymphoid irradiation resulting in local control rate of 95% and longterm disease-free survival (DFS)/overall survival (OS) in 35–86% of cases [13–20]. Long-term follow-up studies from Stanford in 177 patients treated with RT demonstrated a median survival of 13.8 years and 20-year OS of 35% [14]. However, in selected stage I and II patients, deferred therapy is also an acceptable approach, as more than 50% of the patients remained untreated for a median of >6 years and OS was comparable to that seen in reports with immediate treatment [21]. Interestingly, a retrospective analysis from the M.D. Anderson Cancer Center provided evidence for a potential advantage of a combined chemotherapy/ RT approach compared to RT alone with a superior freedom from relapse at 5/10/15 years with no further relapses after 7.5 years [22]. Another phase II trial using a combined modality treatment (CMT) [cyclophosphamide, doxorubicin, vincristine, prednisolone (= CHOP)-Bleomycin/RT] in patients with poor prognostic factors documented a 10-year DFS and OS of 73% and 83%, respectively [23]. Taken together, in patients with stage I/II FL, external beam RT is recommended with curative potential. However, there is no clear consensus concerning the target volume and RT dose. The prospective randomized phase III trial by the German low-grade lymphoma study group comparing extended-field RT versus TLI has been closed in 2007, but results have not been published yet. Currently, a phase III randomized trial on low-dose total body irradiation (TBI) (1.5  Gy) and involved-field RT (26–40  Gy) versus involved-field RT alone is performed by the European Organization for research and treatment of cancer (EORTC). The role of additional chemotherapy and/or rituximab therapy to RT in limited stages I and II is being addressed in ongoing randomized trials. Noteworthy, in the majority of patients the disease is diagnosed at an advanced stage III or IV. In this situation a broad spectrum of therapeutic options are available including a watch and wait period until the disease becomes symptomatic, single agent to combination chemotherapy with or without additional irradiation, chemoimmunotherapy, use of conjugatedradiolabeled monoclonal antibody treatment, high-dose chemotherapy followed by autologous/allogeneic hematopoeitic stem cell transplantation (auto HSCT/allo HSCT), and reduced intensity conditioning (RIC) before allogeneic HSCT. For asymptomatic patients with low-bulk disease an expectant management can be recommended [24]. This approach is based on the results of three

Chapter 11  Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma 

randomized trials demonstrating no survival benefit of immediate compared with deferred treatment until time of progression in the era before rituximab [25–27]. For symptomatic patients, the aim of chemotherapy treatment is to achieve a durable remission. In spite of numerous efforts and the exploration of different conventional chemotherapy strategies resulting in 75–80% responses, the prognosis of FL remained unchanged in recent decades, with a median survival of 8–10 years [28]. In recent years, the introduction of monoclonal antibodies directed against CD20 in combination with chemotherapy (chemoimmuntherapy) as initial therapy has dramatically improved the treatment outcome of FL [29–32]. For example, adding rituximab (R) to CHOP significantly prolonged the time to treatment failure, enhanced overall response rate, prolonged duration of remission, and even translated to superior OS (median survival 12–14 years) when compared to CHOP alone [33, 34]. However, relapses seem to continue after immunotherapeutic treatment. Thus, the concept of maintenance therapy after successful induction therapy is an attempt to prevent the re-emergence of the disease. Maintenance therapy with interferon-a has been evaluated in several clinical trials and was shown to prolong remission duration and OS [35]. However, issues of toxicity coupled with the inconvenient administration have prevented its widespread uptake. Since rituximab couples a high antilymphoma activity with a favorable toxicity profile and was shown to enhance event-free survival (EFS) as maintenance therapy after induction with singleagent rituximab [36, 37] and after chemotherapy induction [38], the effect of rituximab maintenance therapy following first-line induction with rituximab plus chemotherapy is currently being evaluated in an international phase III randomized trial (PRIMA study). In this trial, patients with advanced FL successfully treated with rituximab, plus different chemotherapy schedules are randomized to rituximab maintenance versus observation. Another new treatment approach in patients with advanced FL was the introduction of radioimmunotherapy (complexing radioisotope to a monoclonal antibody) in the first-line treatment of advanced FL. In 90 patients, after 6 cycles of CHOP the additional application of tositumonab/iodine I-131 tositumonab resulted in a promising overall response rate of 91% resulting in an estimated 5-year OS of 87% and progression-free survival (PFS) of 67%, 23% better than CHOP alone [39]. Another single-center phase II-study in 69 patients using tositumonab/iodine I-131 tositumonab yielded in a similar 75% complete response rate resulting in a median PFS of 6.1 years with 40 patients remaining in remission for 4.3–7.7 years [40].

3.  Myeloablative Therapy with Autologous HSCT as Consolidation in First Remission The role of high-dose therapy followed by auto HSCT in patients with FL in first complete remission (CR) or partial remission (PR) has been explored in phase II and three phase III randomized trials. The rationale behind high-dose therapy for up-front treatment is that the intrinsic sensitivity of tumor cells is better early in the course of the disease than after acquirement of drug resistance in response to several cycles of cytotoxic therapy whereas the risks of

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stem cell mobilization and treatment-related toxicity should be lower. When compared to historical controls, phase II trials found extensively prolonged PFS and OS in a substantial proportion of patients receiving auto HSCT [41–45]. Therefore, several groups developed multi-center, randomized phase III trials comparing auto HSCT consolidation after induction chemotherapy versus interferon maintenance or observation. The German Low-grade Lymphoma Study Group (GLSG) recruited 307 previously untreated patients <60 years and patients who responded to induction chemotherapy were randomly assigned to auto HSCT consolidation or interferon-a maintenance. Among 240 evaluable patients, early mortality was below 2.5% in both study arms and the projected 5-year PFS after auto HSCT was 64.7% and only 33.3% in the interferon arm (p<0.0001) [46]. In the Groupe Ouest Est des Leucemies Aigues et autres Maladies du Sang (GOELAMS) study, patients treated with high-dose therapy had a higher response rate and a longer median PFS than patients treated with conventional chemotherapy/interferon-a but this did not translate into a better OS due to an excess of secondary neoplasms (8.5%) after transplantation [47] approved in a recently published analysis of the GLSG with a considerable increased risk of secondary hematologic malignancies after auto HSCT (3.8%) when compared to conventional chemotherapy (0%) [48]. A recently published phase III trial of the Groupe d’ Etude des Lymphomes de l’Adulte (GELA) showed no difference for OS and DFS after a median follow-up of 7.5 years between the standard chemotherapy regimen compared to the auto HSCT arm [49]. Taken together, despite the substantially improved PFS rate in comparison to conventional chemotherapy, long-term results demonstrated no statistically significant difference for OS in favor of first-line auto HSCT due to high recurrence rates and increased risk of secondary malignancies. It seems completely unclear whether relapses are prevented or only postponed after auto HSCT. Therefore, auto HSCT is probably not curative even if applied early in the course of the disease.

4.  Treatment of Relapsed Follicular Lymphoma The treatment options after relapse remain similar to those for first-line therapy. Patients with relapsed asymptomatic disease can be managed expectantly. Defining treatment of relapse should consider the aim of therapy (palliative vs. curative), performance status, age, previous therapy, response to initial therapy, and duration of response. Since, after first recurrence, the natural history of FL is a continuum of repeated chemosensitive relapses of progressively shorter duration and ultimately death from the underlying disease after a median survival of only 4.5 years from first relapse [50], new treatment modalities have been required. In this regard the role of rituximab has been evaluated for relapsed/resistant FL in several trials. In this regard Ghielmini et al. [37] and Hainsworth et al. [36] reported a beneficial effect of rituximab maintenance after response to initial single-agent rituximab treatment associated with little or almost no clinical side effects. A phase III randomized trial in patients with relapsed/ resistant FL evaluated the role of rituximab both in remission induction and in maintenance treatment. A total of 465 patients were randomly assigned to

Chapter 11  Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma 

receive 6 cycles of R-CHOP or CHOP alone. Those in CR/PR were secondly randomized to maintenance rituximab or observation. As a result, chemoimmunotherapy (R-CHOP) yielded in a superior PFS when compared to CHOP alone. Furthermore, rituximab maintenance considerably improved PFS not only after CHOP but also after R-CHOP induction [51].

5.  Myeloablative Therapy with Autologous HSCT in Relapsed/Refractory FL In patients with advanced FL, high-dose chemotherapy with subsequent auto HSCT represents an alternative treatment approach with several phase II studies suggesting a prolonged DFS [52]. Best results are seen when auto HSCT is performed early in the course of disease before patients become chemorefractory. For example, the largest series from Freedman and colleagues reported an estimated 8-year DFS and OS of 42%/66%, respectively [53]. In accordance, Brice et al. demonstrated that patients who underwent auto HSCT had a significantly increased 5-year DFS (42 vs. 16%) and OS (58 vs. 38%) as compared to those who received standard treatment alone [54]. Similar results have been obtained using different hematopoietic stem cell sources, purging methods, and conditioning regimens [55–59]. The only prospective randomized trial addressing the role of auto HSCT in 89 patients with recurrent FL revealed a superior PFS and OS at 2 years after transplant in patients randomized to auto HSCT (55%/71%) compared to those receiving conventional chemotherapy (26%/46%). However, considerable imbalances of clinical risk factors in the three respective subgroups limit the interpretation of these data [60].

6.  Myeloablative Therapy with Allogeneic HSCT The continuous pattern of relapses after auto HSCT without reaching a plateau and the fact that auto HSCT is not feasible when the marrow reserves are inadequate and is poorly effective for patients with refractory disease or extensive bone marrow involvement [61] led to an increased interest in exploring the possibility of an allo HSCT for the treatment of FL. The rationale for conventional allo HSCT is (1) to give maximal anti-tumor therapy to the recipient as part of the conditioning regimen; (2) to ablate the recipient hematopoietic stem cells; (3) to provide space for the incoming hematopoietic cells; (4) to suppress the recipient immune response directed toward the incoming allogeneic cells, thereby facilitating engraftment; and (5) to provide donor-derived tumorreactive T cells capable of mediating graft versus lymphoma (GvL) effects, which may be most effective in indolent lymphoma [62]. In addition, the risk of secondary myelodysplastic syndrome (MDS)/secondary acute myeloid leukemia (sAML) after allo HSCT is presumably negligible since the donorderived stem cells have not been exposed to chemotherapy. The first encouraging results have been published by van Besien in ten patients with refractory (n = 8) or recurrent (n = 2) disease. After predominant conditioning with TBI and use of HLA-identical siblings as donors, eight patients were in CR after a median follow-up of 2.5 years [63]. In 2000, van Besien and coworkers reported the long-term follow-up of this study: 6 years after allo HSCT, only one patient developed disease progression and was in

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Table 11-1.  Conventional conditioning prior to allogeneic HSCT. Author

No. of TBI-based Follow-up TRM Relapse PFS patients conditioning (%) Stem cell source (months) (%) rate (%) (%)

OS (%)

Van Besien [1995]

  10

80

80

BM

30

20

0

80

Van Besien [1998]

113

82

BM

25

40

16

49

49

Mandigers [1998]

  15

100

BM

36

33

13

67

67

Verdonck [1999]

  15

100

BM

25

27

0

70

70

Forrest [2002]

  24

8

BM 67% PB 33% 28

21

0

78

78

Kiss [2003]

  25

0

BM 89% PB 11% 36

NS

NS

79

87

Hosing [2003]

  44

55

BM 41% PB 59% 53

34

19

45

49

Van Besien [2003]

176

68

BM 77% PB 23% 36

24

21

45

51

Peniket [2003]

231

NS

NS

38

25

43

51

Toze [2004]

  29

93

BM

25

24

23

53

58

Yakoub-Agha [2002]   16

81

BM

39

31

0

55

68

60

BM bone marrow, PB peripheral blood, NS not stated

remission 4 years after a second allo HSCT [64]. Up to date, the exact value of allo HSCT can be assessed by analyzing a great amount of studies summarized in Table 11-1 [63, 65, 66, 62, 67–70, 61, 71, 72]. From these results, it appears that conventional allo HSCT was mainly offered to heavily pretreated patients with refractory/recurrent disease and extensive bone marrow involvement. For example, in an observational study in 113 patients with advanced lowgrade lymphoma including 93 patients with FL the 3-year probability of disease recurrence was only 16%, despite 38% of the patients had chemorefractory disease with a DFS and OS being 49% and 49%, respectively. Interestingly, there was only one recurrence among 33 patients monitored for more than 2 years. In this cohort, favorable prognostic factors were use of a TBI-containing pretransplant conditioning regimen, Karnofsky performance status (KPS)³90%, chemotherapy sensitive disease, and age less than 40 years [65]. In recent years, several studies compared the outcome of allogeneic with autologous transplantation. In a retrospective analysis, the International Bone Marrow Transplant Registry (IBMTR) analyzed the data of 904 patients with advanced FL. A total of 176 patients (19%) received allogeneic, 131 (14%) received purged autologous, and 597 (67%) received unpurged autologous transplants. A higher proportion of patients had poor KPS, advanced disease, increased lactate dehydrogenase, bone marrow involvement at transplantation, and chemotherapy resistant disease in the allograft recipients. As a result, the 5-year treatment-related mortality (TRM) was higher in the allo HSCT group (30%) due to infections and graft versus host disease (GvHD) compared with both the purged (14%) and unpurged auto HSCT (8%) group. In strong contrast, the 5-year recurrence rates were considerably lower in the allo HSCT group (21%) when compared to the purged auto HSCT (43%) and unpurged auto HSCT (58%) group providing evidence for a GvL effect resulting in similar estimated 5-year survival rates of 51, 62, and 55%. However, a continuous pattern of relapses was only observed after auto HSCT whereas after allo HSCT only few relapses were detected beyond one year post-transplantation [61].

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165

Taken together, the use of allo HSCT is able to cure patients with advanced FL. The very potent antitumoral effect of allo HSCT has led to encouraging PFS and long-term OS ranging from 49% to 80% accompanied by a low recurrence rate (0–20%) presumably due to a substantial GvL effect [73, 74] and/or lack of tumor contamination of the allogeneic graft [75]. Moreover, over the past decade, advances in supportive care and better patient selection have resulted in improved outcomes for allo HSCT particularly younger ones reducing TRM and severe GvHD [61].

7.  Nonmyeloablative Therapy with Allogeneic HSCT Myeloablative conditioning regimens prior to allogeneic transplantation represent an effective approach to cure patients with advanced FL. However, the use of myeloablative conditioning regimens to treat relapsed and refractory disease has been limited by unacceptable toxicities, particularly due to multiple lines of previous therapy, advanced age of patients, and concomitant diseases. Since FL is most commonly seen in patients with ~60 years, several groups have developed nonmyeloablative/reduced intensity conditioning (RIC) prior to allo HSCT. The aim of this pretransplant regimen is to maximize immunosuppression and to minimize organ toxicity while preserving an adequate antitumor effect by alloreactive donor T cells to ensure stable engraftment and elimination of residual hematopoietic cells of host origin [76]. Recipient immunosuppression is achieved in the main by the use of fludarabine (F) in combination with either low-dose TBI or an alkylating agent such as cyclophosphamide (C), melphalan (M), or busulfan (Bu). Some regimens incorporate additional T cell depletion via antithymocyte globulin (ATG) or alemtuzumab to reduce the risk of acute GvHD. The most important studies available addressing RIC in patients with advanced FL are summarized in Table 11-2 [77–88].

Table 11-2.  Reduced intensity conditioning prior to allogeneic HSCT. Author

No. of Preparative patients regimen

Stem cell source

Follow-up TRM Relapse PFS OS (months) (%) rate (%) (%) (%)

Khouri [2001]

20

FC

PB

21

10

 0

  84

  84

Robinson [2002]

52

Mainly F-based ± ATG/A; BEAM

Mainly PB

 9

22

21

  61

  73

Bertz [2002]

 3

F-based

PB

19

 0

 0

100

100

Ho [2003]

 5

BEAM-AR

PB

17

20

20

  60

  80

Tanimoto [2003]

 8

FC/FBu ± ATG

PB

14

 0

 0

100

100

Escalon [2004]   5

FCR

PB

25

 0

 0

100

100

Faulkner [2004]

28

BEAM-A

PB

17

15.8

10

  69

  69

Morris [2004]

41

FMA

NS

36

11

44

  65

  73

Maris [2005]

47

2Gy TBI ± F

PB

23.8

34

15

  51

  58

Mainly F-based

Mainly PB

23.9

18

NS

  77

  79

Kusumi [2005] 45

F fludarabine, C cyclophosphamide, ATG antithymocyte globulin, A alemtuzumab, BEAM carmustine, etoposide, cytarabine, melphalan, R rituximab, Bu busulfan, M melphalan, TBI total body irradiation, PB peripheral blood, NS not stated

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The first encouraging report of RIC prior to allo HSCT in patients with FL has been published in 1998. After pretransplant conditioning with FC both rapid engraftment and remissions in heavily pretreated, elderly patients could be achieved [89]. The same group reported on 20 patients (median age 51 years; range 31–68 years) who received an RIC regimen consisting of FC; 9 patients additionally received rituximab. All patients had rapid and sustained engraftment and TRM at day 100 was only 10%. The 2-year actuarial DFS/OS were 84%/84%; the rate of acute GvHD grade II–IV and the cumulative chronic GvHD were 20%/64%, respectively. These results are promising, but all patients in this small cohort had a chemosensitive disease, indicating a good-risk group. Moreover, the median observation time (21 months) was short [77]. A large series (n  =  52) of RIC prior to allo HSCT was reported by the European Group for Blood and Bone Marrow Transplantation Registry (EBMTR). After a median follow-up of 283 days, 1-year OS/PFS/TRM/probability of disease progression were 73%/61%/21%/21%, respectively. By multivariate analysis, only disease chemosensitivity at the time of transplant was significantly associated with better PFS. Noteworthy, higher TRM (30.9%) at 2 years highlights the potential toxicity of chronic GvHD and infectious complications after allo HSCT and underscores the need for longer follow-up [78]. In 2004, Morris et al. published results on intensively pretreated patients (n  =  29: FL; n  =  3: lymphoplasmocytoid NHL; n  =  9: CLL) using a T cell depleted graft. The OS at 3 years was 73% and the PFS rate was 65% including patients who achieved remission after DLI application for progressive or persistent disease. However, using a T-cell depleted graft, patients are still at risk of relapse posttransplant with an actuarial relapse rate of 44% at 3 years. Age >45 years and persistent disease status prior to transplant were predictive factors for subsequent relapse [84]. Kusumi et al. also demonstrated the efficacy of RIC in 45 patients with prior auto HSCT and/ or chemoresistant disease. The 3-year OS was 79%, and 3-year PFS were 83 and 64% for the chemosensitive and chemoresistant patients, respectively [86]. More recently, the largest series presenting the long-term outcomes in 73 patients with low-grade lymphoma (n = 61: FL) were reported by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). After a median follow-up of 37 months, 3-year OS/DFS rates were 56%/51%. Among patients in CR, PR, and chemoresistant disease, 3-year OS rates were 66%, 64%, and 32%, while the 3-year EFS rates were 66%, 52%, and 32%, respectively [88]. Taken together use of RIC regimens prior to allo HSCT has shifted some or all of the burden of tumor cell kill from the conditioning regimens to the graft versus tumor/GvL effect. These regimens are less toxic than conventional preparative regimens and allow the treatment of patients with pre-existing organ dysfunction or older patients with comorbid conditions. However, it should be taken into account that most studies of RIC published to date suffer from a relatively short follow-up, inclusion of a heterogeneity of conditioning regimens which makes the comparison difficult. However, all appear to permit durable donor engraftment and the invaluable GvL effect.

8.  Myeloablative Therapy Versus RIC with Allogeneic HSCT In recent years, an increased general use of RIC has been observed: RIC constituted fewer than 10% of the transplants reported in 1997, about 50% in 2000 and 80% in 2002. To evaluate the effect of RIC in FL the outcome

Chapter 11  Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma 

of HLA-identical sibling transplants in 205 patients reported to the IBMTR between 1997 and 2002 has been studied. Conditioning regimens were categorized as myeloablative (ABLAT; n  =  120) or reduced intensity (n  =  80; RIC). ABLAT was defined as TBI containing regimens with single fraction doses ³5 Gy, fractionated doses ³8 Gy, busulfan doses >9 mg/kg, or melphalan doses of >150 mg/m2. RIC were defined as TBI single dose <5 Gy, busulfan doses <9  mg/kg, melphalan doses £150  mg/m2, and fludarabine-based regimens. The median recipient age was 45 (range 28–70) years for ABLAT versus 50 (27–67) years for RIC. After a median follow-up of 49 months for ABLAT and 36 months for RIC, there were no significant differences in acute (37 vs. 40%) or chronic GvHD (44 vs. 53%), TRM (1 year: 23 vs. 20%; 3 years: 25 vs. 24%), PFS (1 year: 68 vs. 63%; 3 years: 65 vs. 55%), or OS (1 year: 72 vs. 72%; 3 years: 70 vs. 64%) between the two groups. However, there was a trend toward an increased risk of disease recurrence after RIC at 1 year (17 vs. 8%, p  =  0.09) reaching statistical significance at 3 years (21 vs. 9%, p  =  0.03) when compared to ABLAT. In multivariate analysis performance status and chemotherapy sensitivity were independently associated with TRM, OS, and PFS, but the type of the conditioning regimen was not [90]. These results have been confirmed in a recently published retrospective analysis in 88 patients including 34 patients with low-grade lymphoma [n  =  18: FL, n  =  16: small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL)] conditioned with conventional myeloablative regimens and an RIC regimen: no statistically significant differences in OS/PFS were detected for patients receiving conventional conditioning (52%/46%) versus RIC-based conditioning (53%/40%). However, RIC was associated with a significantly higher relapse rate (28 vs. 13%, p  =  0.05). These observations must be interpreted within the context of different patient characteristics between the cohorts such that the RIC group was of older age, previous auto HSCT and higher proportion of unrelated donor source [91].

9.  Transformed Follicular NHL Over the time a considerable percentage of FL patients develop disease transformation. Histologic transformation (HT) is defined as the conversion of an FL to intermediate or high-grade lymphoma independent of prior therapy occurring in up to 70% of patients during the course of their disease [92–95]. Despite the fact that a subgroup of patients with limited disease and no previous exposure to chemotherapy may have a relatively long-term survival [96], most series reported a poor prognosis with median survival durations of less than 1 year [94], [97]. Therefore, high-dose therapy followed by auto HSCT has been applied to these poor prognosis patients in an attempt to improve survival rates. In a report from the St. Bartholomew’s Hospital, 27 patients received TBI/cyclophosphamide as pretransplant regimen with autologous BM (n = 24) or peripheral blood stem cell (n = 3) support. With a median follow-up of 2.4 years, 14/27 remain alive and disease-free; 5 are alive and free of disease at more than 4 years with a median OS of 8.5 years [98]. The role of auto HSCT in the management of FL in transformation has been extensively investigated. Several studies found DFS/OS rates of 30–81%. Age >60 years, elevated LDH, chemorefractory disease, and HT beyond 18 months conferred a worse outcome [56], [59], [99–103].

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From these studies, it was concluded that especially younger patients who attain CR after high-dose therapy benefit from auto HSCT. Presently, it remains speculative whether these results could be further improved by the use of radioimmunotherapy [104], [105] or allo HSCT.

10.  Conclusion In general, for FL the goal of therapy is to maintain the best quality of life and to initiate treatment only when patients develop symptomatic disease. Despite the benign course of FL and any data demonstrating any benefit for early therapy, patients are generally treated precociously early in the course of their disease. Currently, for first-line treatment in early stages I and II, external beam RT is recommended with curative potential. The role of additional chemotherapy or rituximab therapy to RT in early stages I and II is being investigated in ongoing trials. In case of advanced disease, there is no universal agreement as to the optimal first-line or subsequent therapy. Up to date, in younger patients with good performance status, chemoimmunotherapy using R-CHOP with maintenance rituximab might be regarded as standard therapy based on data demonstrating higher response rates, longer durations of response, improved survival, lower rate of histological transformation, and high stem cell mobilization ability for potential later use for auto HSCT. However, there are promising results obtained by the early use of radioimmunoconjugates, too. Up to date there are no randomized trials comparing chemoimmunotherapy with radioimmunoconjugates as front-line therapy in advanced FL. In elderly patients with symptomatic disease, single agent chemotherapy with chlorambucil or rituximab might be appropriate. In case of relapse, asymptomatic disease is not necessarily an indication for treatment and patients can be managed expectantly. For symptomatic FL, single agent rituximab and chemoimmunotherapy followed by rituximab maintenance are widely used in this setting. For younger patients who are suitable candidates for transplantation high-dose therapy followed by auto HSCT continued to be offered in chemoresponsive relapsed disease. However, despite high response rates and improved PFS auto HSCT is associated with an increased risk of relapse. Results with myeloablative allo HSCT unequivocally demonstrated a reduction in relapse/disease progression but minimal late recurrences did not translate into an improved OS compared with auto HSCT yet due to high TRM. However, over the past decade, advances in supportive care and better patient selection have resulted in improved outcomes for allo HSCT reducing TRM. For patients with chemoresistant disease younger than 50 years, conventional allo HSCT is probably the best procedure if patients have an HLA-identical sibling. RIC has substantially reduced up-front toxicity and data seem highly encouraging with regard to efficacy. Nonmyeloablative treatment probably yields a similar cure rate with a lower TRM but higher relapse rate. Despite the fact that prospective randomized trials comparing this strategy with conventional allo HSCT are missing and most of the studies available lack a longer follow-up, RIC is actually the most common approach for allo HSCT in FL. Up to date, the best pretransplant conditioning regimen remains to be evaluated. On the one hand, TBI-based conditioning regimens were associated with a statistically significant decrease in disease recurrence

Chapter 11  Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma 

but on the other hand use of TBI was shown to increase TRM providing a rationale for the development of radiolabeled monoclonal antibodies as part of conditioning regimens. Peripheral blood stem cells should be recommended as stem cell source because of a faster neutrophil and platelet recovery and immune reconstitution when compared to BM-derived stem cells [106]. Acknowledgments  The authors highly acknowledge Marianne Engelhard (University of Essen, Department of Radiation Oncology, Hufelandstr. 55, D-45122 Essen, Germany) for helpful discussions and critical cross-reading of the chapter.

References 1. Greenlee RT, Murray T, Bolden S et al (2000) Cancer statistics, 2000. CA Cancer J Clin 50:7–33 2. Jemal A, Siegel R, Ward E et al (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66 3. Weisenburger DD (1994) Epidemiology of non-Hodgkin’s lymphoma: Recent findings regarding an emerging epidemic. Ann Oncol 5:19–24 4. Chiu BC, Weisenburger DD (2003) An update of the epidemiology of non-Hodgkin’s lymphoma. Clin Lymphoma 4:161–168 5. Clarke CA, Glaser SL (2002) Changing incidence of non-Hodgkin lymphomas in the United States. Cancer 94:2015–2023 6. The non-Hodgkin’s lymphoma classification P: A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma, 1997, pp 3909–3918 7. Groves FD, Linet MS, Travis LB et  al (2000) Cancer surveillance series: NonHodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 92:1240–1251 8. Armitage JO, Weisenburger DD (1998) New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780–2795 9. Grulich AE, Vajdic CM (2005) The epidemiology of non-Hodgkin lymphoma. Pathology 37:409–419 10. Harris NL, Jaffe ES, Diebold J et al (1999) World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues: Report of the Clinical Advisory Committee Meeting Airlie House, Virginia, November 1997, pp 3835–3849 11. Ott G, Katzenberger T, Lohr A et al (2002) Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3. Blood 99:3806–3812 12. Solal-Celigny P, Roy P, Colombat P, et al (2004) Follicular lymphoma international prognostic index. Blood 104:1258–1265 Epub 2004 May 4 13. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA et  al (1994) Clinical stage 1 non-Hodgkin’s lymphoma: Long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69:1088–1093 14. Mac Manus MP, Hoppe RT (1996) Is radiotherapy curative for stage I and II lowgrade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14:1282–1290 15. Stuschke M, Hoederath A, Sack H et  al (1997) Extended field and total central lymphatic radiotherapy in the treatment of early stage lymph node centroblasticcentrocytic lymphomas: Results of a prospective multicenter study. Study Group NHL-fruhe Stadien. Cancer 80:2273–2284

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F. Heinzelmann et al. 16. Sack H, Hoederath A, Stuschke M et al (1998) Radiotherapy of follicle center lymphoma. Results of a German multicenter and prospective study. Members of the Study Group “NHL-early stages”. Strahlenther Onkol 174:178–185 discussion 186 17. Neumann H, Blanck H, Koch R et al (2003) Follicle centre lymphoma: Treatment results for stage I and II. Strahlenther Onkol 179:840–846 18. Ott OJ, Rodel C, Gramatzki M et al (2003) Radiotherapy for stage I–III nodal lowgrade non-Hodgkin’s lymphoma. Strahlenther Onkol 179:694–701 19. Petersen PM, Gospodarowicz M, Tsang R et al (2004) Long-term outcome in stage I and II follicular lymphoma following treatment with involved field radiation therapy alone. J Clin Oncol 22(Suppl 14S):6521 20. Guadagnolo BA, Li S, Neuberg D et al (2006) Long-term outcome and mortality trends in early-stage, Grade 1–2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 64:928–934 21. Advani R, Rosenberg SA, Horning SJ (2004) Stage I and II follicular nonHodgkin’s lymphoma: Long-term follow-up of no initial therapy. J Clin Oncol 22:1454–1459 22. Besa PC, McLaughlin PW, Cox JD et al (1995) Long term assessment of patterns of treatment failure and survival in patients with stage I or II follicular lymphoma. Cancer 75:2361–2367 23. Seymour JF, Pro B, Fuller LM et al (2003) Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin’s lymphoma. J Clin Oncol 21:2115–2122 24. Gribben JG (2007) How I treat indolent lymphoma. Blood 109:4617–4626 25. Young RC, Longo DL, Glatstein E et al (1988) The treatment of indolent lymphomas: Watchful waiting v aggressive combined modality treatment. Semin Hematol 25:11–16 26. Brice P, Bastion Y, Lepage E et al (1997) Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 15:1110–1117 27. Ardeshna KM, Smith P, Norton A et  al (2003) Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: A randomised controlled trial. Lancet 362:516–522 28. Horning SJ (2000) Follicular lymphoma: Have we made any progress? Ann Oncol 11:23–27 29. Fisher RI, LeBlanc M, Press OW et al (2005) New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447–8452 30. Marcus R, Imrie K, Belch A et al (2005) CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417–1423 31. Herold M, Haas A, Srock S et al (2007) Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J Clin Oncol 25:1986–1992 32. Salles GA, Foussard C, Nicolas M et  al (2004) Rituximab added {alpha} IFN + CHVP improves the outcome of follicular lymphoma patients with a high tumor burden: To first analysis of the GELA-GOELAMS FL-2000 randomized trial in 359 patients, Blood (Ash Annual Meeting Abstracts), 104, abstract 160 33. Hiddemann W, Kneba M, Dreyling M et al (2005) Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advancedstage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725–3732

Chapter 11  Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma  34. Hiddemann W, Hoster E, Buske C et al (2006) Rituximab is the essential treatment modality that underlies the significant improvement in short and long term outcome of patients with advanced stage follicular lymphoma – A 10 year analysis of GLSG trials, Blood (Ash Annual Meeting Abstracts), 108, abstract 483 35. Rohatiner AZ, Gregory WM, Peterson B et al (2005) Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 23:2215–2223 36. Hainsworth JD, Litchy S, Shaffer DW et al (2005) Maximizing therapeutic benefit of rituximab: Maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin’s lymphoma – a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23:1088–1095 37. Ghielmini M, Schmitz SF, Cogliatti SB et  al (2004) Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly × 4 schedule. Blood 103:4416–4423 38. Hochster HS, Weller E, Gascoyne RD et al (2005) Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): Results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B, Blood (Ash Annual Meeting Abstracts), 106, abstract 349 39. Press OW, Unger JM, Braziel RM et al (2006) Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: Five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 24:4143–4149 40. Kaminski MS, Tuck M, Estes J et  al (2005) 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441–449 41. Freedman AS, Gribben JG, Neuberg D et al (1996) High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 88:2780–2786 42. Horning SJ, Negrin RS, Hoppe RT et al (2001) High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: Results of a phase II clinical trial. Blood 97:404–409 43. Seyfarth B, Kuse R, Sonnen R et al (2001) Autologous stem cell transplantation for follicular lymphoma: No benefit for early transplant? Ann Hematol 80:398–405 44. Voso MT, Martin S, Hohaus S et al (2000) Prognostic factors for the clinical outcome of patients with follicular lymphoma following high-dose therapy and peripheral blood stem cell transplantation (PBSCT). Bone Marrow Transplant 25:957–964 45. Ladetto M, Corradini P, Vallet S et al (2002) High rate of clinical and molecular remissions in follicular lymphoma patients receiving high-dose sequential chemotherapy and autografting at diagnosis: A multicenter, prospective study by the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Blood 100:1559–1565 46. Lenz G, Dreyling M, Schiegnitz E et al (2004) Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: Results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104:2667–2674 47. Deconinck E, Foussard C, Milpied N et al (2005) High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: A randomized multicenter study by GOELAMS. Blood 105:3817–3823 48. Lenz G, Dreyling M, Schiegnitz E et  al (2004) Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22:4926–4933 49. Sebban C, Mounier N, Brousse N et al (2006) Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem

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F. Heinzelmann et al. cell transplantation in untreated patients with advanced follicular lymphoma: The GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 108:2540–2544 50. Johnson PW, Rohatiner AZ, Whelan JS et al (1995) Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 13:140–147 51. van Oers MH, Klasa R, Marcus RE et al (2006) Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 108:3295–3301 52. Tse WW, Lazarus HM, Van Besien K (2004) Stem cell transplantation in follicular lymphoma: Progress at last? Bone Marrow Transplant 34:929–938 53. Freedman AS, Neuberg D, Mauch P et al (1999) Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 94:3325–3333 54. Brice P, Simon D, Bouabdallah R et al (2000) High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11:1585–1590 55. Rohatiner AZ, Johnson PW, Price CG et  al (1994) Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol 12:1177–1184 56. Bastion Y, Brice P, Haioun C et al (1995) Intensive therapy with peripheral blood progenitor cell transplantation in 60 patients with poor-prognosis follicular lymphoma. Blood 86:3257–3262 57. Bierman PJ, Vose JM, Anderson JR et al (1997) High-dose therapy with autologous hematopoietic rescue for follicular low-grade non-Hodgkin’s lymphoma. J Clin Oncol 15:445–450 58. Apostolidis J, Gupta RK, Grenzelias D et al (2000) High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: Long-term clinical and molecular follow-up. J Clin Oncol 18:527–536 59. Cao TM, Horning S, Negrin RS et  al (2001) High-dose therapy and autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission: The Stanford University experience. Biol Blood Marrow Transplant 7:294–301 60. Schouten HC, Qian W, Kvaloy S et al (2003) High-dose therapy improves progressionfree survival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918–3927 61. van Besien K, Loberiza FR Jr, Bajorunaite R et al (2003) Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102:3521–3529 62. Verdonck LF (1999) Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade non-Hodgkin’s lymphoma: Updated results of the Utrecht experience. Leuk Lymphoma 34:129–136 63. van Besien KW, Khouri IF, Giralt SA et al (1995) Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: The case for aggressive management. J Clin Oncol 13:1096–1102 64. van Besien K, Champlin IK, McCarthy P (2000) Allogeneic transplantation for low-grade lymphoma: Long-term follow-up. J Clin Oncol 18:702–703 65. van Besien K, Sobocinski KA, Rowlings PA et al (1998) Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92:1832–1836 66. Mandigers CM, Raemaekers JM, Schattenberg AV et  al (1998) Allogeneic bone marrow transplantation with T-cell-depleted marrow grafts for patients with poorrisk relapsed low-grade non-Hodgkin’s lymphoma. Br J Haematol 100:198–206 67. Forrest DL, Thompson K, Nevill TJ et  al (2002) Allogeneic hematopoietic stem cell transplantation for progressive follicular lymphoma. Bone Marrow Transplant 29:973–978

Chapter 11  Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma  68. Yakoub-Agha I, Fawaz A, Folliot O et  al (2002) Allogeneic bone marrow transplantation in patients with follicular lymphoma: A single center study. Bone Marrow Transplant 30:229–234 69. Kiss TL, Panzarella T, Messner HA et al (2003) Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and marrow transplantation in patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant 31:73–78 70. Hosing C, Saliba RM, McLaughlin P et al (2003) Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin’s lymphoma. Ann Oncol 14:737–744 71. Peniket AJ, Ruiz de Elvira MC, Taghipour G et al (2003) An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: Allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 31:667–678 72. Toze CL, Barnett MJ, Connors JM et al (2004) Long-term disease-free survival of patients with advanced follicular lymphoma after allogeneic bone marrow transplantation. Br J Haematol 127:311–321 73. van Besien KW, de Lima M, Giralt SA et  al (1997) Management of lymphoma recurrence after allogeneic transplantation: The relevance of graft-versus-lymphoma effect. Bone Marrow Transplant 19:977–982 74. Ratanatharathorn V, Uberti J, Karanes C et al (1994) Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with nonHodgkin’s lymphoma. Blood 84:1050–1055 75. Gribben JG, Freedman AS, Neuberg D et al (1991) Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 325:1525–1533 76. Champlin R, Khouri I, Kornblau S et  al (1999) Reinventing bone marrow transplantation: Reducing toxicity using nonmyeloablative, preparative regimens and induction of graft-versus-malignancy. Curr Opin Oncol 11:87–95 77. Khouri IF, Saliba RM, Giralt SA et al (2001) Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98:3595–3599 78. Robinson SP, Goldstone AH, Mackinnon S et al (2002) Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: An analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100:4310–4316 79. Bertz H, Illerhaus G, Veelken H et  al (2002) Allogeneic hematopoetic stem-cell transplantation for patients with relapsed or refractory lymphomas: Comparison of high-dose conventional conditioning versus fludarabine-based reduced-intensity regimens. Ann Oncol 13:135–139 80. Ho AY, Devereux S, Mufti GJ et  al (2003) Reduced-intensity rituximab-BEAMCAMPATH allogeneic haematopoietic stem cell transplantation for follicular lymphoma is feasible and induces durable molecular remissions. Bone Marrow Transplant 31:551–557 81. Tanimoto TE, Kusumi E, Hamaki T et al (2003) High complete response rate after allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimens in advanced malignant lymphoma. Bone Marrow Transplant 32:131–137 82. Escalon MP, Champlin RE, Saliba RM et al (2004) Nonmyeloablative allogeneic hematopoietic transplantation: A promising salvage therapy for patients with nonHodgkin’s lymphoma whose disease has failed a prior autologous transplantation. J Clin Oncol 22:2419–2423 83. Faulkner RD, Craddock C, Byrne JL et al (2004) BEAM-alemtuzumab reducedintensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients. Blood 103:428–434

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F. Heinzelmann et al.   84. Morris E, Thomson K, Craddock C et al (2004) Outcomes after alemtuzumabcontaining reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood 104:3865–3871   85. Maris MB, Sandmaier BM, Storer B et  al (2005) Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for relapsed or refractory follicular lymphoma, Blood (Ash Annual Meeting Abstracts), 106, abstract 1130   86. Kusumi E, Kami M, Kanda Y et al (2005) Reduced-intensity hematopoietic stemcell transplantation for malignant lymphoma: A retrospective survey of 112 adult patients in Japan. Bone Marrow Transplant 36:205–213   87. Khouri IF, Saliba RM, Hosing CM et al (2005) Autologous stem cell (AUTO) vs non-myeloablative allogeneic transplantation (NMT) after high-dose rituximab (HD-R)-containing conditioning regimens for relapsed chemosensitve follicular lymphoma (FL), Blood (Ash Annual Meeting Abstracts), 106, abstract 48   88. Vigouroux S, Michallet M, Porcher R et  al (2007) Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: A survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica 92:627–634   89. Khouri IF, Keating M, Korbling M et  al (1998) Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817–2824   90. Van Besien K, Carreras J, Zhang M-J et al (2005) Reduced intensity vs myeloablative conditioning for HLA matched sibling transplantation in follicular lymphoma, Blood (Ash Annual Meeting Abstracts), 106, abstract 656   91. Rodriguez R, Nademanee A, Ruel N et al (2006) Comparison of reduced-intensity and conventional myeloablative regimens for allogeneic transplantation in non-Hodgkin’s lymphoma. Biol Blood Marrow Transplant 12:1326–1334   92. Acker B, Hoppe RT, Colby TV et  al (1983) Histologic conversion in the nonHodgkin’s lymphomas. J Clin Oncol 1:11–16   93. Horning SJ, Rosenberg SA (1984) The natural history of initially untreated lowgrade non-Hodgkin’s lymphomas. N Engl J Med 311:1471–1475   94. Schouten HC, Bierman PJ, Vaughan WP et al (1989) Autologous bone marrow transplantation in follicular non-Hodgkin’s lymphoma before and after histologic transformation. Blood 74:2579–2584   95. Horning SJ (1993) Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol 20:75–88   96. Yuen AR, Kamel OW, Halpern J et al (1995) Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13:1726–1733   97. Cullen MH, Lister TA, Brearley RI et  al (1979) Histological transformation of non-Hodgkin’s lymphoma: A prospective study. Cancer 44:645–651   98. Foran JM, Apostolidis J, Papamichael D et  al (1998) High-dose therapy with autologous haematopoietic support in patients with transformed follicular lymphoma: A study of 27 patients from a single centre. Ann Oncol 9:865–869   99. Friedberg JW, Neuberg D, Gribben JG et  al (1999) Autologous bone marrow transplantation after histologic transformation of indolent B cell malignancies. Biol Blood Marrow Transplant 5:262–268 100. Berglund A, Enblad G, Carlson K et al (2000) Long-term follow-up of autologous stem-cell transplantation for follicular and transformed follicular lymphoma. Eur J Haematol 65:17–22 101. Chen CI, Crump M, Tsang R et al (2001) Autotransplants for histologically transformed follicular non-Hodgkin’s lymphoma. Br J Haematol 113:202–208 102. Williams CD, Harrison CN, Lister TA et al (2001) High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular nonHodgkin’s lymphoma: A case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19:727–735

Chapter 11  Treatment Strategies for Follicular Center Cell Non-Hodgkin’s Lymphoma  103. Corradini P, Ladetto M, Zallio F et  al (2004) Long-term follow-up of indolent lymphoma patients treated with high-dose sequential chemotherapy and autografting: Evidence that durable molecular and clinical remission frequently can be attained only in follicular subtypes. J Clin Oncol 22:1460–1468 104. Kaminski MS, Zelenetz AD, Press OW et al (2001) Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 19:3918–3928 105. Davies AJ, Rohatiner AZ, Howell S et al (2004) Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 22:1469–1479 106. Korbling M, Anderlini P (2001) Peripheral blood stem cell versus bone marrow allotransplantation: Does the source of hematopoietic stem cells matter? Blood 98:2900–2908

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Chapter 12 The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia Mickey Liao and Gary J. Schiller

1.  Introduction Favorable-risk acute myeloid leukemia (AML) is a subgroup of AML that has been shown to have clinically unique behavior and improved response to therapy based on distinct molecular biology. Traditional post-remission therapies, including intensive consolidation chemotherapy as well as autologous or allogeneic transplantation, have been associated with improved clinical outcomes in this subpopulation. Still, the term favorable-risk incorrectly implies a high likelihood of long-term survival. In fact, most studies show that among patients in first complete remission (CR1) whose disease is characterized by favorable-risk features, long-term survival is achieved in only 40–60%. Notwithstanding that nearly half such patients may sustain relapse, there has been little enthusiasm for autologous or allogeneic stem cell transplantation as post-remission treatment for patients with otherwise favorable disease features on the basis of an excessively high rate of treatment-related morbidity and mortality. Given the remarkable advances in supportive care and immunoprophylaxis with stem cell transplantation over the last several decades and a shift toward risk-adapted therapy, standard post-remission strategies for favorable-risk AML in CR1 are being re-evaluated.

2.  Favorable-Risk AML Historically, AML has been broadly classified morphologically, distinguishing unique histological subtypes that are uniformly defined by an inappropriate increase in immature myeloid progenitor cells. Considering its molecular and cytogenetic complexity, AML is better defined according to these features that give insight into disease biology. Cytogenetic-risk categories are distinguished by response to conventional chemotherapeutic agents in terms of induction of complete remission (CR) and leukemia-free survival (LFS). The recent World Health Organization (WHO) Classification system emphasizes the cytogenetic and molecular diversity of AML, and oncology cooperative groups have

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_12, © Springer Science + Business Media, LLC 2003, 2010

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developed categories of disease based on cytogenetic profiles as poor-risk, intermediate-risk, and favorable-risk AML. Favorable-risk AML is defined by specific cytogenetic abnormalities including t(8;21); t(15;17); and inv(16). Numerous newly identified structural defects, including mutations of the FMSrelated tyrosine kinase 3 (FLT3) gene and nucleophosmin, member 1 (NMP1) gene, may also function as independent prognostic markers but are beyond the scope of this chapter [1]. In the early 1980s, a group of patients was identified in whom there was a distinct response to standard AML induction therapy. These patients were all subclassified as having acute myelomonocytic leukemia with abnormal bone marrow eosinophilia. A retrospective statistical analysis of this subgroup revealed a markedly improved response rate to cytarabine-/anthracyclinebased induction chemotherapy [2]. At the same time, a unique cytogenetic abnormality involving chromosome 16 was identified among those patients who were most likely to achieve a CR. A larger study evaluating over 30 patients with morphologic features consistent with acute myelomonocytic leukemia with abnormal eosinophils and association with inv(16) or t(16;16) cytogenetic abnormality would later corroborate these earlier findings [3]. Given the promising predictive value of cytogenetic analysis, a large retrospective study of previous acute leukemia trials from 1972 to 1980 was performed and again identified improved clinical outcomes in those patients whose leukemia was characterized by abnormalities involving chromosome 16. Interestingly, another subgroup for whom similarly impressive responses to both induction and consolidation therapy was identified – patients with t(8;21). This finding was later reproduced by a large prospective analysis from the Cancer and Leukemia Group B (CALGB) of over 1,000 patients with newly diagnosed AML [4]. In patients whose leukemia was characterized by abnormalities of chromosome 16 or t(8;21), a significantly improved prognosis, as compared to those with normal karyotype, was observed. In that review, an 85% CR rate was achieved in those with abnormalities of chromosome 16 and a 91% CR rate was reported for those with t(8;21), following standard induction chemotherapy [5]. Initial investigation of clinical outcomes in patients with AML characterized by t(15;17) cytogenetic abnormality produced variable results. However, since the introduction of all-trans retinoic acid (ATRA) into standard therapy for acute promyelocytic leukemia (APL), those patients with t(15;17) have similarly been identified as likely to achieve long-term LFS and are thus included among those with favorable-risk acute leukemia [6]. Several trials have now confirmed the clinical observation that cytogenetics play a major predictive role, not only in response to therapy, but in long-term survival as well. The CALGB demonstrated a significant increase in LFS and overall survival (OS), in patients whose disease was characterized by either inv(16) or t(8;21) chromosomal abnormalities, to single-agent cytarabine-based consolidation chemotherapy [7]. A large study from the United Kingdom, enrolling more than 1,600 child and adult patients with either de novo or secondary AML, concluded that age and cytogenetics were the most important predictors of relapse rate and OS [8]. Patients with favorable-risk cytogenetics who achieve a CR with induction therapy can typically expect a 5-year OS rate that approaches 60% [5]. Although this result is generally considered favorable, one must appreciate that nearly half of the patients with newly diagnosed, the so-called favorable-risk AML, will relapse of disease.

Chapter 12  The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia 

3.  Molecular Pathogenesis The predictive capacity of favorable cytogenetics suggests that a molecular abnormality is directly tied to the sensitivity to conventional therapeutic agents and consequently a clinical outcome better than that which can be achieved for other types of AML. In turn, understanding the genetic defects and associated mechanisms of action could potentially improve outcome further. Molecular studies of favorable-risk AML have identified multiple genes that encode either DNA-binding transcription factors or the regulatory components of transcriptional complexes [9]. The best characterized cytogenetic abnormality involves the t(15;17) translocation associated with APL. The t(15;17) translocation involves formation of the transgene PML-RARa and subsequent generation of a fusion protein which inhibits DNA binding of CCAAT/enhancer binding proteina (C/EBPa), a transcription factor involved in the regulation of myelopoiesis. ATRA has since been introduced as a therapeutic agent that targets the chimeric protein and allows for normal myeloid differentiation [10]. In addition to PML-RARa, other molecular subgroups to consider with favorable-risk AML include the core-binding factor (CBF) abnormalities. The CBF DNA binding target is in the promoter/enhancer region of many genes expressed in hematopoietic cells, hence the pathogenic role in leukemia. The associated transcription factor complex, AML1-CBFb, was originally discovered through cloning of the t(8;21) translocation and identification of the AML1 gene. The transcription factor complex regulates a number of hematopoiesis-specific genes as well as the normal development of the hematopoietic system through activation of transcription as well as recruitment of coactivators. The t(8;21) translocation joins the N-terminal part of the AML1 gene on chromosome 21 with the C-terminal portion of the ETO gene on chromosome 8. The resultant fusion protein retains the ability to bind AML1-targeted sequences through its interactions with CBFb, however, instead functions as a repressor of transcription through recruitment of a nuclear corepressor complex [11]. Furthermore, AML1-ETO may lead to down-regulation of C/EBPa [12]. Abnormalities with chromosome 16 involve the same transcription factor complex. The CBFb subunit on chromosome 16q22 is fused to the smooth muscle myosin heavy chain gene MYH11 on chromosome 16p13. The resultant chimeric product, CBFb-MYH11, directly represses AML1-mediated transcription by recruiting AML1 into functionally inactive complexes within the cytoplasm [13].

4.  Post-remission Therapy Patients whose AML is characterized by favorable-risk cytogenetic abnormalities represent not only a cohort of patients whose disease is more responsive to current induction regimens, but also a subgroup in whom intensive post-remission therapy may be increasingly curative. Although a variety of post-remission strategies have been utilized, studies have consistently demonstrated superior responses in the favorable-risk groups, as compared to the poor-risk groups, regardless of the therapy selected. Treatment of APL, in particular, has undergone some of the most remarkable changes. With CR rates of 80–90% and OS

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rates of 70–75% since the introduction of ATRA therapy to standard induction chemotherapy, the role of myeloablative therapy in CR1 has virtually been eliminated [14–16]. Even when APL is further risk stratified based on white blood cell count and platelet count, those at highest risk still have an OS rate of greater than 70% [17]. One could argue for more intensive chemotherapy in an attempt to further improve OS in the setting of APL. However, it would be difficult to demonstrate a superior result with myeloablative therapy for disease characterized by t(15;17) given the risk of some degree of transplant-related morbidity and mortality balanced against the remarkable survival data with standard induction chemotherapy plus ATRA. Furthermore, As2O3 has also already been shown to have significant activity in APL and is currently the treatment of choice for relapsed APL. Two studies have additionally demonstrated CR rates of over 80% when arsenic trioxide was used as a single agent in newly diagnosed APL [18,19]. However, in patients with t(8;21) or inv(16) favorable-risk cytogenetic abnormalities, long-term clinical outcomes are less impressive and the optimal post-remission strategy remains unclear. In a small study published in 1991, a single cycle of high-dose cytarabine/ daunorubicin consolidation therapy was found most likely to achieve a favorable response in those patients with favorable-risk cytogenetics [20]. In a much larger trial of older adults with AML from the United Kingdom, induction therapy followed by randomization to either no therapy or further consolidation chemotherapy, also showed a significantly improved LFS in patients with AML characterized by favorable-risk cytogenetics as compared to those with poor-risk features [8]. Finally, in a trial of four cycles of variably dosed cytarabine-based consolidation chemotherapy, the group with favorable-risk cytogenetics again was most likely to achieve an improved clinical outcome. In fact, the greatest improvement in LFS rate was identified in the group of patients with favorable-risk cytogenetics receiving the highest doses of cytarabine consolidation. Improved outcomes in favorable-risk groups are not only limited to dose-intensified consolidation chemotherapy, but can also be extended to myeloablative therapy followed by transplantation. In a study from France, patients with favorable-risk cytogenetic abnormalities achieved a superior clinical outcome with allogeneic or autologous transplantation as compared to those with poor-risk cytogenetics [21]. Thus, regardless of whether the postremission strategy included chemotherapy or transplantation, the best results were routinely identified in the favorable-risk group. Presently, allogeneic stem cell transplantation is the recommended approach only in those patients with features of poor-risk leukemia, for whom all strategies yield poor results. However, the role of transplantation in favorable-risk AML needs to be further investigated since it is conceivable that the most dose-intensive approach would be the most likely to achieve a favorable response.

5.  Stem Cell Transplantation Historically, adult patients with AML in CR1 have been treated with doseintense consolidation chemotherapy based on evidence documenting a superior median LFS when compared to less intensive post-remission therapy. However, the rate of sustained LFS can vary widely, from 15% to 60%, largely depending on the cytogenetic-risk group [22–26]. As a consequence,

Chapter 12  The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia 

a variety of other post-remission strategies have been implemented including myelosuppressive maintenance therapy, multiple and prolonged cycles of consolidation chemotherapy, as well as autologous or allogeneic transplantation. Transplantation has generally been reserved for those patients with poor-risk AML, including those patients with deletion 5q or 7q, trisomy 8, t(6;9), t(9;22), those with clinical features of adverse prognosis such as antecedent history of hematologic disease, or those patients with refractory or relapsed leukemia, in whom, given the dismal outcomes, transplantation affords the best potential for anti-leukemic effect despite the lack of impressive survival statistics. Meanwhile, patients whose disease is characterized by favorable-risk cytogenetics have generally been discouraged from pursuing myeloablative therapy given the favorable outcomes of intensive chemotherapy alone [27]. Although there are no data to support survival benefit, review of the literature consistently demonstrates a decreased relapse rate following stem cell transplantation as compared to intensive consolidation chemotherapy alone. Unfortunately, post-remission therapy with transplantation has historically been associated with an unacceptably high treatment-related mortality (TRM), with upwards of 20–30% TRM in allogeneic transplantation and 10–20% TRM in autologous transplantation, discouraging routine practice [28]. However, improved supportive care has increased the tolerability of transplantation over the past decades. These advancements have altered the risk–benefit ratio, and suggest a reappraisal of the role of stem cell transplantation in favorable-risk AML.

6.  Autologous Stem Cell Transplantation Autologous stem cell transplantation (ASCT) allows a larger, unselected population of patients, including potentially patients up to 70 years of age, to derive the benefits of a myeloablative preparative therapy without incurring the higher risk of transplant-related morbidity and mortality associated with allogeneic transplantation, including acute and chronic graft-versus-host disease (GVHD). ASCT was first utilized as a salvage therapy for relapsed disease in the late 1970s, when numerous studies showed it was capable of inducing a CR in most patients and was associated with a prolonged LFS in the range of 20–50% [29]. Given the encouraging results in relapsed leukemia, the role of ASCT for AML in CR1 was pursued. Numerous studies have since evaluated the safety and efficacy of autologous transplantation compared with intensive consolidation chemotherapy or no further therapy with AML in CR1 [22–24,30–33]. Although none of the studies have demonstrated a significant overall survival benefit, two large studies have shown a meaningful difference in LFS (see Tables 12-1 and 12-2). In 1986, the European Organization for Research and Treatment of Cancer (EORTC) in conjunction with the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups conducted a large prospective trial of three post-remission strategies to examine LFS and OS [22]. A total of 941 patients entered the trial; although, only 623 patients achieved a CR. Furthermore, there was a significant drop-out rate, leaving only 343 patients who received their intended post-remission therapy. In the intent-to-treat (ITT) analysis, LFS at 4 years was 48% in the ASCT group and 30% in the chemotherapy-alone group with relapse rates of 41 and 57%, respectively. Although the differences in results for LFS and relapse

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Table 12-1.  LFS with ASCT for AML in CR1. Study

ASCT (%)

Chemotherapy (%)

P-value

Zittoun et al. [22]   All patients – 4-year DFS

48

30

0.05

Burnett et al. [23]   All patients – 7-year DFS   Favorable risk

53 70

40 46

0.04 0.04

Cassileth et al.   All patients – 4 years [24]   Favorable risk [35]

35 71

35 35

NS 0.04

Harousseau et al. [32]   All patients – 4-year DFS

44

41

NS

Tsimberidou et al. [31]   All patients – 3-year DFS

42

33

NS

Breems et al. [33]   All patients – 5-year DFS

35

37

NS

NS non-significant

Table 12-2.  OS with ASCT for AML in CR1. Study

ASCT (%)

Chemotherapy (%)

P-value

Zittoun et al. [22]   All patients – 4-year OS

56

46

NS

Burnett et al. [23]   All patients – 7-year OS   Favorable risk

57 74

45 51

NS NS

Cassileth et al. [24]   All patients – 4-year OS [35]

43

52

0.05

Harousseau et al. [32]   All patients – 4-year OS

50

55

NS

Tsimberidou et al. [31]   All patients – 3-year DFS

58

46

NS

Breems et al. [33]   All patients – 5-year OS

45

55

NS

NS non-significant

rate were statistically significantly, there was no significant difference in OS. Unfortunately, these results were not further stratified by cytogenetic risk. The Medical Research Council Leukaemia Working Parties undertook a prospective trial (MRC AML 10), for which the principal aim was to assess the value of high-dose therapy supported by either ASCT or allogeneic stem cell transplantation (alloSCT) for AML in CR1. The outcomes of ASCT were first reported in 1998 with follow-up alloSCT results published in 2002 [23,34]. Unfortunately, there again was a high drop-out rate in the ASCT arm, with only 126 of 190 (66%) of the assigned patients receiving the intended therapy. Nevertheless, when evaluated based on an ITT analysis, LFS at 7 years was found to be 54% in the ASCT group versus 40% in the group assigned no

Chapter 12  The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia 

further therapy and the relapse rate was 37 and 58%, respectively. Both the differences in LFS and relapse rates were again statistically significant findings. Furthermore, a subgroup analysis of the data based on cytogenetic risk, revealed an added benefit in LFS and relapse rate. In favorable-risk patients, LFS improved to 70% with ASCT versus 48% in the group assigned no further therapy and relapse rate improved to 25% versus 49%, respectively. Interestingly, there was one study which demonstrated a modest survival benefit, albeit, surprisingly identified in the chemotherapy alone arm. In a large American Intergroup trial also reported in 1998, ASCT or alloSCT were compared to high-dose cytarabine in young adults with AML in CR1 in a manner similar to the previously described EORTC/GIMEMA schema [24,35]. In the ITT analysis, LFS at 4 years was not found to be statistically different. However, there was a trend toward a marginally improved OS. The OS rate at 4 years was 43% for the ASCT arm and 52% in the chemotherapy alone arm which was statistically significant. However, when risk-stratified by cytogenetics, LFS rates for favorable-risk AML were found to be 71% for ASCT and 35% for chemotherapy alone which was also significantly different, but in favor of ASCT. Unfortunately, overall survival data were not available stratified by cytogenetic risk. These large studies help support a potential role for ASCT in favorable-risk AML in CR1. When stratified by cytogenetic-risk group, the improvements in the relapse rate and LFS with ASCT as compared to chemotherapy alone are compelling. However, these results have to be interpreted with caution given the complex study designs inherent to transplantation trials, inconsistent patient populations including considerable patient withdrawal and treatment crossover, and perhaps most importantly, lack of survival benefit.

7.  Allogeneic Stem Cell Transplantation The mechanism behind the success of allogeneic peripheral stem cell transplantation (alloSCT) is multi-factorial by way of delivery of myeloablative conditioning therapy, similar to what is used in autologous transplantation, in combination with an additional element of immunologic stimulation associated with the allograft itself – that is, graft versus leukemia effect. Nevertheless, OS rates have not been demonstrated to be significantly superior compared to what is achieved with an initial strategy of intensive consolidation chemotherapy with the possibility of salvage alloSCT in relapse. Furthermore, alloSCT is associated with a significantly elevated TRM rate. Consequently, although AML remains the most common indication for alloSCT, its role in adults has largely been restricted to those patients with poor cytogenetic risk, refractory, and relapsed AML in whom all treatment options yield disappointing results. Although to date, there is no general recommendation for alloSCT in favorable-risk AML in CR1, improved transplantation technique and supportive care allow for reinvestigation. The impact of cytogenetics on outcomes of alloSCT was first described by Slovak et al. in 2000 [35]. Five-year estimates for overall OS in favorable-, intermediate-, and poor-risk cytogenetic groups were shown to be 63%, 52%, and 44%, respectively. Those results established

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the predictive role of karyotype on clinical outcome of alloSCT in AML. A study by Kim et  al. published in 2005 further illustrated that cytogenetic risk carried more discriminative power than even clinical disease status at time of presentation in predicting prognosis following alloSCT [36]. AlloSCT has additionally been associated with improved rates of relapse when compared to chemotherapy alone or ASCT. However, given the favorable outcomes associated with intensive consolidation chemotherapy alone, in combination with a historically significant TRM associated with alloSCT, data have been sparse with respect to the effect of alloSCT specifically in those with favorable-risk AML in CR1. Several large studies investigating the role of alloSCT as post-remission therapy have been published. Although, results have not routinely been stratified by cytogenetic risk (see Tables  12-3 and 12-4). When considering all cytogenetic-risk groups, no survival benefit has been demonstrated when comparing alloSCT to ASCT. However, several studies have shown a significant improvement in LFS. In the BGMT 87 study, Reiffers et al. report in 1996 on the outcomes of 240 previously untreated younger patients who were consolidated with alloSCT or, if an HLA-matched donor was not available, randomized to ASCT versus intensive consolidation chemotherapy [30]. LFS at 3 years was found to be 66% for the alloSCT group and 42% for the ASCT group, which was statistically significant. However, there was no significant difference in overall survival. The previously discussed MRC AML 10 trial also evaluated the value of alloSCT. When reviewed based on an ITT analysis, LFS at 7 years was found to be 50% in the alloSCT group versus 42% in the group assigned no further therapy with a relapse rate of 36 and 52%, Table 12-3.  LFS with AlloSCT for AML in CR1. Study

AlloSCT (%)

ASCT (%)

P-value

Zittoun et al. [22]   All patients – 4-year LFS

55

48

NS

50

42

0.001

53 63

66 52

NS NS

Cassileth et al. [24]   All patients – 4-year LFS

43

35

n/a

Suciu et al. [37]   All patients – 4-year LFS   Favorable risk (t(8;21)/inv 16)

52 62

42 66

0.04 NS

Jourdan et al. [42]   All patients – 10-year LFS   Favorable risk [t(8;21), inv16, t(15;17)]

n/a 51

n/a 68

n/a NS

Harousseau et al. [32]   All patients – 4-year LFS

44

44

NS

Reiffers et al. [30]   All patients – 3-year LFS

66

42

0.05

Tsimberidou et al. [31]   All patients – 3-year LFS

n/a

n/a

n/a

Burnett et al. [34]   All patients – 7-year LFS   Favorable risk   t(8;21)/inv(16)   t(15;17)

n/a not available; NS non-significant

Chapter 12  The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia 

Table 12-4.  OS with AlloSCT for AML in CR1. Study

AlloSCT (%)

ASCT (%)

P-value

Zittoun et al. [22]   All patients – 4-year OS

59

56

NS

56

50

NS

63 75

77 72

NS NS

Cassileth et al. [24]   All patients – 4-year OS

46

43

NS

Suciu et al. [37]   All patients – 4-year OS   Favorable risk [t(8;21)/inv16]

58 n/a

50 n/a

NS n/a

Jourdan et al. [42]   All patients   Favorable risk [t(8;21), inv16, t(15;17)]

51 51

43 74

NS NS

Harousseau et al. [32]   All patients – 4-year OS

53

50

NS

Reiffers et al. [30]   All patients – 3-year OS

n/a

n/a

n/a

Tsimberidou et al. [31]   All patients – 3-year OS

58

50

NS

Burnett et al. [34]   All patients – 7-year OS   Favorable risk   t(8;21)/inv(16)   t(15;17)

n/a not available; NS non-significant

respectively [34]. Both the differences in LFS and relapse rates were statistically significant findings while overall survival was again not significantly different. Finally, in 2003 Suciu et al. reported on the outcomes of over 2,100 patients who were assigned to alloSCT or ASCT consolidation therapy in CR1 based on the availability of an HLA-matched donor. ITT analysis again demonstrated a significantly decreased relapse rate and improved DFS in the alloSCT group versus ASCT although no survival benefit was seen [37]. Despite the statistical evidence for LFS benefit in several studies, the variability of results and overall lack of significant survival advantage among the available published data was described well in a large systematic analysis of consolidation therapies for adult AML conducted by Visani et al. in 2006 [39]. Finally, a large meta-analysis, conducted by Yanada et  al. in 2005, did collectively demonstrate a statistically significant OS benefit with alloSCT for AML in CR1 [40]. However, upon further stratification of the patients by cytogenetic-risk, survival benefit was limited only to those patients with intermediate- and poor-risk cytogenetic groups and not extended to the favorable-risk group. A recent study by the HOVON/SAKK collaborative study group in 2007 readdressed the question as to whether the use of alloSCT in all patients with AML in CR1 had a favorable impact on LFS as well as OS [41]. Over 1,000 patients, all less than 55 years of age, were recruited. LFS at 4 years was found to be 48% among patients with a donor and 37% for those without, while OS at 4 years was found to be 54 and 46%, respectively. Although there was a statistically significant difference in LFS, there was no significant difference in OS. When stratified by cytogenetic risk, significant LFS was again limited only to the intermediate- and poor-risk cytogenetic

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groups. A meta-analysis of the data from the HOVON/SAKK study and three previously published large studies from the EORTC, MRC, and BGMT was also prepared [34,37,42]. The cumulative results of donor versus no donor outcomes for AML in CR1 demonstrated a statistically significant LFS benefit observed particularly in younger patients and in patients without favorable-risk cytogenetics. Additionally, a significant survival advantage was again identified. But, further subgroup analysis similarly restricted the survival benefit to those patients without favorable-risk cytogenetics with improved outcomes most prominent in younger patients. Despite evidence for LFS and modest aggregate OS benefit with alloSCT for AML in CR1, when further stratified by cytogenetic risk, these advantages have not been reproduced within the favorable-risk group. However, there are a number of limitations within the available published data including a lack of randomization inherent to trials involving alloSCT. Additionally, given the low compliance rate often associated with the alloSCT treatment arms and an effort to analyze data based on ITT, one could also argue that the current data may under-represent the full benefit of alloSCT. Nevertheless, the sum of these studies gives credence to the value of early alloSCT from an HLA-identical sibling donor for patients with AML in CR1 in younger patients with intermediate- or poor-risk cytogenetics. Consolidation therapy with alloSCT in patients with AML in CR1 and favorable-risk cytogenetics, however, does not share the same LFS or survival benefits. Consequently, alloSCT remains an area of investigation in patients with AML in CR1 with favorable-risk cytogenetics and cannot currently be considered a part of standard care.

8.  Refractory Acute Myeloid Leukemia Despite therapeutic advances, up to 20–30% of AML patients will never be able to achieve a CR. The only curative option for those patients remains an allogeneic transplantation. Although transplantation is reasonable to consider in any patient with primary refractory AML, it is important to recognize that cytogenetic risk remains an important predictor of clinical outcome in a procedure that is traditionally associated with a high TRM as well as a high risk of relapse. Although publications are few, a review by Song et  al. in 2005 concluded that a number of predictive factors could be utilized, including karyotype, to weigh the risks and benefits of proceeding with alloSCT [43]. Given the unique underlying biology and associated improved clinical outcomes, transplantation should always be considered for younger patients with a matched sibling donor and favorable-risk refractory AML.

9.  Relapsed Acute Myeloid Leukemia Once patients have relapsed, myeloablative therapy with stem cell rescue remains the most durable treatment option regardless of cytogenetic-risk group. AlloSCT with a matched sibling donor is associated with a long-term LFS upwards of 30–40%. Although improved clinical outcomes have been shown in those with increased duration of CR1, superior data when stratified by

Chapter 12  The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia 

cytogenetic-risk are not available to support its use specifically in the favorablerisk group. Meanwhile, ASCT has been associated with a variable LFS rate of 25–40% [44–46]. However, here cytogenetic-risk group has been shown to be of some prognostic value. In a study by Linker et al. in 2002, the most significant prognostic factor for outcome in their study was cytogenetics, where all seven patients with t(15;17) undergoing ASCT had long-term LFS [47]. These findings were corroborated by a CALGB study of 50 patients with relapsed AML in CR2 who underwent ASCT, where patients with t(15;17) cytogenetic abnormality were found to have a significantly improved event-free survival (EFS) of 74% as compared to all other patients with an EFS of only 22% [48]. While transplantation is generally avoided with APL in CR1, these data support a substantial benefit with ASCT when applied in the salvage setting. Those patients with AML who relapse after myeloablative therapy have a poor prognosis independent of cytogenetic-risk group. The interval from the time of first transplant to relapse remains the most important predictor of outcome. Second transplantation in those with favorable-risk relapsed AML associated with an interval from first transplant to relapse of greater than 7 months could be considered in younger patients with good performance status. As one might expect, this subset represents a highly restricted group.

10.  Acute Myeloid Leukemia in the Elderly AML in the elderly has practically been defined as AML in those patients greater than or equal to 60 years of age, approximately 5–10 years less than the median age at presentation of all AML patients. Outcomes in this subpopulation are largely influenced by either TRM or therapeutic resistance. While increasing age certainly contributes to increased risk of TRM, therapeutic resistance is largely influenced by leukemia-cell cytogenetics [49]. Favorablerisk cytogenetics are uncommon in this patient population, however when present, continue to predict a more favorable outcome [50]. Nevertheless, given the particularly high TRM in this age group, alloSCT has been categorically excluded in the elderly. Although ASCT as a treatment option is not absolutely contraindicated, it would generally represent the exception rather than the rule. Current thinking suggests immunologically mediated graft-versus-leukemia (GVL) may outweigh the role of high-dose chemotherapy as the principal mechanism of an anti-leukemic effect in transplantation [51]. Based upon this philosophy, the use of reduced-intensity conditioning (RIC) SCT has gained increasing popularity. Given the decreased TRM in association with increased anti-leukemic effect, RIC SCT may serve a particular role in the older patient with good risk factors who is generally excluded from alloSCT. Although there remains a paucity of data on this subject, there are studies which endorse its use in the elderly population [52,53]. Mohty et al. reported on the first donor versus no donor analysis of RIC alloSCT in older patients with AML [54]. Although the study included only a limited number of patients, there was a suggestion of an improved LFS in the donor arm. A subsequent study from M.D. Anderson in 2007 also demonstrated a trend toward improved OS; however, this study was similarly limited by low patient enrollment [55]. Subgroup analysis by cytogenetic risk was not available for either study. Despite the observed reduction in TRM and suggestion of survival benefit

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with RIC SCT, one has to be cognizant of other associated morbidities with stem cell transplantation, including risk of GVHD and infection, which remain comparable to traditional allogeneic stem cell transplantation rates. Its use thus far has been focused on the geriatric population. However, it would be of value to evaluate its role specifically in favorable-risk AML as well.

11.  Conclusions The role of transplantation in AML has traditionally been limited to those patients with poor-risk cytogenetic features, clinical features of adverse prognosis including antecedent hematologic disease, and refractory or relapsed leukemia. Identification of karyotype as a prominent prognostic factor has led to re-evaluation of the optimal post-remission strategy, including in particular the role of myeloablative therapy followed by stem cell transplantation. The improved understanding of disease biology in AML has been followed by a shift toward a risk-adapted approach to therapy. Although transplantation in favorable-risk AML has repeatedly been shown to offer significant LFS benefits, these results have previously been tempered by the significant associated TRM. Modern day transplantation technique and supportive care have dramatically improved the TRM, shifting the balance of risk and benefit. Post-remission therapy with ASCT in those patients with favorable-risk AML can be expected to impart an improved rate of LFS superior to intensive consolidation chemotherapy alone. Although survival benefit has not yet been demonstrated, given the improvements in transplant care, this post-remission strategy may be appropriate with careful patient selection. Meanwhile, the data with alloSCT for favorable-risk AML in CR1 are lacking and require continued investigation. It should not be considered part of standard care at this time. An area of ongoing research includes the use of RIC SCT where early observations show a trend toward improved clinical outcomes in the elderly population. Stem cell transplantation has re-emerged as a therapeutic option for favorable-risk AML. Future studies should continue to be designed with an emphasis on the biological heterogeneity that defines AML to facilitate therapeutic advances.

References   1. Mrozek K, Marcucci G, Pascha P et al (2007) Clinical relevance of mutations and gene expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 109:431–448   2. Le Beau MM, Larson RA, Bitter MA, Vardiman JW, Golomb HM, Rowley JD (1983) Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association. N Engl J Med 309:630–636 3. Larson RA, Williams SF, Le Beau MM, Bitter MA, Vardiman JW, Rowley JD (1986) Acute myelomonocytic leukemia with abnormal eosinophils and inv (16) or t(16;16) has a favorable prognosis. Blood 68:1242–1249 4. Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwars CG, Arthur DC et al (2002) Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325–4336

Chapter 12  The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia  5. Larson RA, Le Beau MM, Vardiman JW, Testa JR, Golomb HM, Rowley JD (1983) The predictive value of initial cytogenetic studies in 148 adults with acute nonlymphocytic leukemia: a 12-year study (1970–1982). Cancer Genet Cytogenet 10:219–236 6. Tallman MS, Antersen JW, Schiffer CA, Applebau RR, Feusner JH, Woods WG et al (2002) All-trans retinoic acid in acute promyelocytic leukemia: long term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 100(76):1083–1091 7. Schlenk RF, Benner A, Hartmann F, del Valle F, Weber C, Pralle H et al (2003) AML Study Group Ulm (AMLSG ULM). Risk-adapted postremission therapy in acute myeloid leukemia: results of the German multicenter AML HD93 treatment trial. Leukemia 17:1521–1528 8. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al (1998) On behalf of the Medical Research Council Adult and Children’s Leukemia Working Parties. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. Blood 92:2322–2333 9. Look AT (1997) Oncogenic transcription factors in the human acute leukemia. Science 278:1059–1064 10. Warrell RP Jr, De Thé H, Wang Z-Y, Degos L (1993) Acute promyelocytic leukemia. N Eng J Med 329:177–189 11. Wang J, Hoshino T, Redner RI, Kajigaya S, Liu JM (1997) Novel human nuclear receptor co-repressor: cloning and identification as a binding partner for the ETO proto-oncoprotein. Blood 90(Suppl 1):245a. Abstract 12. Schiller GJ (2005) Clinical and biological features of favorable-risk acute myelogenous leukemia – is favorable-risk AML really favorable? Leukemia 19:326–328 13. Kanno Y, Kanno T, Sakakura C, Bae SC, Ito Y (1998) Cytoplasmic sequestration of the polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor alpha (CGFalpha) subunit by the leukemia-related PEBO2/CGFbeta-SMMHC fusion protein inhibits PEBP2/CBF-mediated transactivation. Mol Cell Biol 18:4252–4261 14. Fenaux P, Le Deley MC, Castaigne S, et al. European APL 91 Group (1993) Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood 82:3241–3249 15. Fenaux P, Chastang C, Chomienne C et al (1995) European APL Group. Treatment of newly diagnosed acute promyelocytic leukemia (APL) by all transretinoic acid (ATRA) combined with chemotherapy the European experience. Leuk Lymphoma 16:431–437 16. Tallman MS, Anderson JW, Schiffer CA et al (2002) All-trans retinoic acid acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 100:4298–4302 17. Sanz MA, Lo Coco F, Martin G (2000) Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96:1247–1253 18. George B, Mathews V, Vishwabandhya A, et al (2004) Arsenic trioxide (As2O3) in the treatment of patients with newly diagnosed acute promyelocytic leukemia (APML) – toxicity and outcome [abstract]. Blood 104(pt 1):254a. Abstract 889 19. Ghavamzadeh A, Alimoghaddam K, Ghaffari H, et  al (2004) Treatment of new cases of acute promyelocytic leukemia by arsenic trioxide [abstract]. Blood 104(pt 1): 116a. Abstract 396 20. Phillips GL, Reece DE, Shepherd JD, Barnett MJ, Brown RA, Frei-Lahr DA et al (1991) High dose-cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. Blood 77:1429–1435

189

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M. Liao and G.J. Schiller 21. Ferrant A, Frassoni LF, Prentice HG, Cahn JY, Blaise D, Reiffers J et al (1997) on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study. Blood 90: 2931–2938 22. Zittoun RA, Mandelli F, Willemze R et al (1995) Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 332:217–223 23. Burnett AK, Goldstone AH, Stevens RMF et al (1998) Randomized comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukemia in first remission: results of MRC AML 10 trial. Lancet 351:700–708 24. Cassileth PA, Harrington DP, Appelbaum FR et al (1998) Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 339:1649–1666 25. Bloodfield CD, Lawrence D, Byrd JC et al (1998) Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 58:4173–4179 26. Heil G, Krauter J, Kirchner H et al (2000) Risk adapted induction and consolidation therapy including autologous peripheral blood stem cell transplantation (PBSCT) in adults with de novo AML £ 60 years. Blood 96(Suppl 1):522a (Abstr. 224) 27. Byrd JC, Dogde RK, Carroll A, Baer MR, Edwards C et al (1999) Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol 17:3767–3775 28. Tallman MS, Nabhan C, Camitta BM (2005) Acute Myeloid Leukemia. In: Williams ME, Kahn MJ (eds) ASH-SAP American Society of Hematology SelfAssessment Program, 2nd edn. Blackwell, Malden, MA, p 211 29. Spellberg B, Schiller GJ (1999) Autologous bone marrow transplantation in acute leukemia. Hematol Oncol Clin North Am 13:919–938 30. Reiffers J, Stoppa AM, Attal M et al (1996) Allogeneic vs autologous stem cell transplantation vs chemotherapy in patients with acute myeloid leukemia in first remission: the BGMT 87 study. Leukemia 10:1874–1882 31. Tsimberidou AM, Stavroyianni N, Viniou N et al (2003) Comparison of allogeneic stem cell transplantation, high-dose cytarabine, and autologous peripheral stem cell transplantation as postremission treatment in patients with de  novo acute myelogenous leukemia. Cancer 97:1721–1723 32. Harousseau J, Cahn JY, Pignon B, Witz F et al (1997) Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood 8:2978–2986 33. Breems DA, Boogaerts MA, Dekker AW et al (2005) Autologous transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukemia in first complete remission: a prospective randomized Dutch-Belgian Hemato-Oncology Co-operative Group (HAVON) and Swiss Group for Clinical Cancer Research (SAKK) trial. Br J Haematol 128:59–65 34. Burnett AK, Wheatley K, Goldstone AH et  al (2002) On behalf of the Medical Research Council Adult and Paediatric Working Parties. The value of allogeneic bone marrow transplant in patients with acute myeloid leukemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol 118:385–400 35. Slovak ML, Kopecky KJ, Cassileth PA et al (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 96:4075–4083

Chapter 12  The Role of Transplantation in Favorable-Risk Acute Myeloid Leukemia  36. Kim DH, Sohn SK, Kim JG et  al (2005) Parameters for predicting allogeneic PBSCT outcome of acute myeloid leukemia: cytogenetics as presentation versus disease status at transplantation. Ann Hematol 84:25–32 37. Suciu S, Mandeli F, De Witte T et  al (2003) For the EORTC and GIMEMA Leukemia Groups. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMA AML-10 trial. Blood 102:1232–1240 38. Keating S, de Witte T, Suciu S et  al (1998) The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis on the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA. European Organization for Research and Treatment of Cancer. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. Br J Haematol 102:1344–1353 39. Visani G, Olivieri A, Malagola M et  al (2006) Consolidation therapy for adult acute myeloid leukemia: a systematic analysis according to evidence based medicine. Leuk Lymphoma 47:1091–1102 40. Yanada M, Matsuo K, Emi N, Naoe T (2005) Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission. Cancer 103:1652–1658 41. Cornelissen JJ, van Putten WLJ, Verdonck LF et al (2007) Results of a HOVON/ SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 109:3658–3666 42. Jourdan E, Boiron J-M, Dastugue N et al (2005) Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience. J Clin Oncol 23:7676–7684 43. Song KW, Lipton J (2005) Is it appropriate to offer allogeneic hematopoietic stem cell transplantation to patients with primary refractory acute myeloid leukemia? Bone Marrow Transplant 36:183–191 44. Meloni G, Vignetti M, Avvisati G et  al (1996) BAVC regimen and autograft for acute myelogenous leukemia in second complete remission. Bone Marrow Transplant 18:693–698 45. Lioure B, Witz F, Deconninck E et  al (1997) Autologous stem cell transplantation (ASCT) represents the best consolidation therapy for acute myelogenous leukemia (AML) in second complete remission (CR): a retrospective study of the GOELAMS group. Blood 90(Suppl 1):384a (Abstr. 1710) 46. Califaretti N, Davidson M, Abraham R et  al (1998) Autologous bone marrow transplant (ABMT) for acute myelogenous leukemia (AML) in second or subsequent remission. Blood 92(Suppl 1):294a (Abstr. 1203) 47. Linker CA, Damon LE, Ries CA et al (2002) Autologous stem cell transplantation for advanced acute myeloid leukemia. Bone Marrow Transplant 29:297–301 48. Linker C, George S, Hurd D et al (2001) Autologous stem cell transplantation for acute myeloid leukemia in second remission-CALGB 9620. Blood 98(Suppl 1): 689a (Abstr. 2881) 49. Estey E (2007) Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 25:1908–1915 50. Estey E (2006) General approach to, and perspectives on clinical research in, older patients with newly diagnosed acute myeloid leukemia. Semin Hematol 43:89–95 51. Kolb HJ, Schattenberg A, Goldman JM et al (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients: European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86:2041–2050

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M. Liao and G.J. Schiller 52. Niederwieser D, Gentilini C, Hegebart U et  al (2005) Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity conditioning in patients with acute leukemias. Crit Rev Oncol Hematol 56:275–281 53. Cornelissen JJ, Löwenberg B (2005) Role of allogeneic stem cell transplantation in current treatment of acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 151–155 54. Mohty M, De Lavallade H, Ladaique P et al (2005) The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison. Leukemia 19:916–920 55. Estey E, de Lima M, Tibes R et  al (2007) Prospective feasibility analysis of reduced intensity conditioning regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia and high-risk myelodysplasia syndrome. Blood 109:1395–1400

Chapter 13 Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults David I. Marks

1.  Introduction The results of all therapies for adults with acute lymphoblastic leukaemia remain disappointing. Five year survival of the 1929 intensively treated patients in the UKALL XII/ECOG 2993 study was 39% [1]. Chemotherapy is toxic and prolonged; this study reported a 12% 2-year non-relapse mortality in patients without donors. There is a feeling that chemotherapy cannot be pushed much further. Younger (<25–30 years) patients are being treated on more intensive “pediatric” protocols with more asparaginase but there are no mature multicenter data available to evaluate the efficacy of this approach. B cell antibodies are being pursued by a number of groups, nelarabine is being trialled upfront for T cell disease and the early experience with forodesine looks promising but increasing the doses or intensity of the standard drugs seems unlikely to produce significant survival benefits. There has been a better definition of adverse risk factors [2] in recent times, enabling us to target patients likely to fail chemotherapy with our most aggressive therapies. The 5-year overall survival of patients with t(4;11) low hypodiploidy/near triploidy or >5 abnormalities were 24, 22 and 28%, respectively making these patients valid targets for more aggressive approaches. In addition, a major German study of MRD at 9 time points in the first year of acute lymphoblastic leukaemia (ALL) therapy, has found that patients with molecular MRD detectable at week 16 have a very poor outcome (12 vs. 66%) [3] making these patients logical candidates for trials of different approaches including upfront allografting (Table 13-1).

2.  Rationale and the Graft-Versus-Leukaemia Effect Allogeneic stem cell transplantation allows considerably higher doses of chemoradiotherapy to be administered enabling a greater initial leukemic cell kill. However, careful examination of the (considerable) evidence reveals an important graft-versus-leukaemia effect. Given that this was the first disease in which a GvL effect was described, and given the multiple studies showing a

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_13, © Springer Science + Business Media, LLC 2003, 2010

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Table 13-1.  Studies comparing sibling allografting in CR1 acute lymphoblastic leukemia with chemotherapy and/or autologous SCT. Author

Patient no

Donor survival

No donor survival (%)

p value

Attal [20]

572

46% at 5 years

31

0.04

Hunaulta [21]

198

75% at 5 years

40

0.027

804

54% at 5 years

44

0.02

b

Goldstone  [1] a

Eligibility for randomisation: age >35, WCC >30, non-T cell, poor-risk cytogenetics, no CR at day 35 b Donor vs. No-donor analysis (chemotherapy only-this arm was superior to autograft)

reduced relapse rate in allograft patients, it is surprising that many haematologists and even transplanters deny or underrate this effect [29, 31]. Harnessing the allogeneic GvL effect and using the positive benefits of acute and chronic GVHD are essential for curing the high-risk patient or patients with positive MRD prior to transplant. Passweg and colleagues showed 10 years ago that patients with acute, chronic, or both acute and chronic GVHD had a 2.5fold reduction in relapse risk on multivariate analysis (RR = 0.40) [4]. Other studies have shown that chronic GVHD has more of an effect than acute GVHD. Some forms of T cell depletion prevent grade II–IV acute GVHD but there may still be a significant incidence of chronic GVHD; this may be a strategy worth further investigation. Further evidence will come from trials of RIC allografting where there is greater reliance on the GVL effect. There are no large-scale mature data available, but the CIBMTR will be analysing the outcome of >200 RIC allografts for ALL in 2009.

3.  Conditioning Regimens There are no randomised studies comparing conditioning regimens and many large studies have missed opportunities to compare regimens. There are very few data on non-TBI-containing regimens and the survival data does not recommend their use. The City of Hope and Stanford groups have a 20 year experience with etoposide (60 mg/kg) and 13.2 Gy of total body irradiation given in 9 fractions and have excellent survival data [5]. Marks and colleagues from the CIBMTR compared this regimen with standard cyclophosphamide and TBI. Cyclophosphamide and 12  Gy of TBI produced markedly inferior survival compared to etoposide-containing or higher-dose TBI regimens [6]. However, if >13 Gy TBI was given, etoposide/ TBI was not superior to cyclophosphamide/TBI. Transplant-related mortality was (perhaps surprisingly) not higher in the etoposide TBI arm although this is undoubtedly a more toxic regimen. The issue of mucositis will be discussed later in this chapter.

4.  Sibling Allografting in First Remission There are methodological difficulties establishing the efficacy of allograft in adults with ALL. A simple comparison of outcome in patients who received an allograft with those who did not would not suffice, as the allograft group

Chapter 13  Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults 

195

are on average fitter and had to survive a certain time in remission in order to have an allograft. To overcome these biases, donor vs. no-donor analyses were devised. These too are flawed in that they may underestimate the potential benefit of allograft as many patients with matched sibling donors do not proceed to allograft and indeed in many it was never the intention to do so. Nonetheless, they have become widely accepted and if they do show an advantage one can be confident that such a difference exists [7]. Sibling allografting has long been established as the therapy of choice in high risk ALL (Hoelzer criteria). Two French studies compared allografting with chemotherapy and autografting, and there were significant differences in overall survival [21]. A meta-analysis support this [30]. The results of the recent very large international ALL study have provided clarity. All patients <50 years, who were fit for transplant and had a matched sibling donor, were eligible to have an allograft. It was a donor vs. no-donor analysis, which is good at avoiding some known biases towards transplant but which may underestimate the positive effect of allograft. Survival was superior in the donor arm compared with patients without a donor. Subsequently, when chemotherapy was shown to be superior to autografting the comparison was with chemotherapy-treated patients but the donor arm was about 10% superior. However, this was not the case in the high-risk group, most of whom where >35 years. The donor arm is 6% better at 5 years but the difference was not significant. There was still excellent protection against relapse (35 vs. 67%) but survival was not improved because of a high non-relapse mortality (29% at 1 year and 39% at 2 years). The investigators concluded that if the allogeneic effect could be harnessed more safely in this group allograft in high-risk patients with ALLl in CR1 might be worth pursuing. The TRM in low-risk (younger) patients was a disappointing 20% at 2 years; improving this should also be the focus of research efforts.

5.  Unrelated Donor SCT in First Remission Encouraging results of sibling allografting and studies showing that UD SCT can produce similar results to sibling allografts for leukaemia have lead to many investigating the role of UD SCT in high-risk CR1 ALL (Table 13-2). Marks and colleagues from the CIBMTR recently described 169 adult patients with a median age of 33 years who underwent UD SCT. One hundred and fifty-seven were at highrisk and 93 had multiple high-risk factors. Overall survival was 40%. Multivariate analysis showed that the following factors affected survival: WCC at diagnosis, HLA mismatch, >8 weeks to CR1 and T cell depletion. This latter finding was a surprise and as there were only Table 13-2.  Studies of the outcome of unrelated donor stem cell transplantation for adult patients with acute lymphoblastic leukemia in CR1. Author

Patient no

Age (years)

Survival (%)

TRM

Grade 2–4 acute/chronic (%)

Marks [22]

169

33

39

42%

50/43

Dahlke [8]

  38

23

44

NK

36/23

Kiehl [7]

  45

29

45

NK

33/NK

NK not known or not specifically stated

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16 patients with T cell depletion (with a variety of techniques) it cannot be regarded as a definite finding. Patel and colleagues have analysed 55 patients (median age 25 years) who had T-depleted UD SCT for high-risk ALL in CR1 mainly using in vivo alemtuzamab (Patel et al. in press). About half of these patients were taken out of UKALL XII to have an “off-protocol” allograft. Survival was an excellent 59% at 3 years and there was a clear plateau with no events after 2 years. The incidences of grade II–IV, grade III–IV and chronic GVHD were 25, 7 and 22%, respectively. It is difficult to compare the two series but the UK series had a low TRM (19%) and good survival, albeit in a younger population. Kiehl and colleagues from Germany reported 97 patients, 87 of whom received TCD, who had a TRM of 31% and grades III–IV acute GVHD in only 15% [8]. On a similar note, Dahlke and colleagues compared sibling and unrelated donor allografts in 38 and 46 patients in CR1, respectively and found that survival was the same in the 2 groups (44 vs. 46%, p = NS) [9]. Unrelated donor SCT clearly has a growing role in this disease. The promising results from (albeit) limited data and the finding that survival is now similar to allografts with sibling donors make it reasonable to perform prospective trials of this therapeutic modality. However, patients should be entered in studies so that we learn how to optimise this procedure and the data do not support the use of unrelated donor SCT as standard therapy for ALL in CR1.

6.  The Role of RIC Allografting We have been slow to investigate this transplant modality in adult ALL. The mistaken notion that the GvL effect was less important in this disease and the view that conditioning regimens had to contain TBI may have led to this attitude. Consequently, it has initially been performed in patients who could not tolerate myeloablative conditioning because of comorbidity or in elderly patients who have little prospect of cure with chemotherapy (Table 13-3). There are no large scale prospective studies of RIC allografting in this disease. The data with us are relatively small retrospective series of patients with various stem cell sources and heterogeneous disease states. The largest series from the European Blood and Marrow Transplantation Group (EBMT), reported in 2008 by Mohty and colleagues describes 97 patients, 70 of whom had died at the time of analysis [10]. Two-thirds received stem cells from sibling Table 13-3.  Studies of the outcome of reduced intensity conditioning allogeneic stem cell transplantation for adult ALL. Author a

Patient no

Sibs/UDs (%)

CR1/CR2/other (%)

Regimens

Survival

Mohty  [9]

97

67/33

29/26/45

Various

21% at 2 year

Martino [23]

27

56/44

15/41/44

Various

31% at 2 year

Massenkeil [24]

 9

NK

NK

Flu/Bu/ATG

40% at 3 year

Forman [25]

22

33/67

48/19/33

Flu/Mel

77% at 1 year

Hamaki [26]

33

20/13

19/0/14

Flu/Bu/ATG

30% EFS 1 year

a

41% Philadelphia positive. Survival was 52% at 2 years if patient was in CR1 Reported transplant-related mortality ranged from 4 to 27% Flu fludarabine, Bu busulfan, ATG antithymocyte globulin, Mel melphalan, UD unrelated donor

Chapter 13  Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults 

donor and one-third from unrelated donors. Survival at 2 years was 21% in the whole group but promisingly exceeded 50% in those with high-risk disease. Patients in CR1 did significantly better with 52% surviving disease free at 2 years. Patients with chronic GVHD had superior OS (RR 0.4, p < 0.01). There were a variety of RIC regimens used (39% had ATG and 24% had a low-dose TBI-containing regimen) but these are not precisely described in the paper. A smaller series using a uniform protocol (fludarabine and melphalan) was described by the City of Hope group using sibling donors in and unrelated donors [11]. Given the disease status and risk status of the group, the TRM was low (10%) and survival of 70% at 1 year was promising. Longer followup is needed.

7.  Allografting for Relapsed Disease Selected series have produced some reasonable results for allografting in second complete remission using sibling or unrelated donors. However, the situation in a multicentre setting is less optimistic. Fielding and colleagues described the outcome of 607 adult ALL patients who relapsed and only 7% of these patients survive median term. Forty-two patients had matched sibling allografts and survival at 3 years was 23%. Even more disappointingly, 65 patients received stem cells from unrelated donors and only 16% survived at 3 years [12]. Only two-thirds of patients who relapse will achieve CR2 and many will relapse before an appropriate donor is found. I strongly recommend doing a preliminary unrelated donor search in all intensively treated adult ALL patients without sibling donors at diagnosis and referral of the patient to a specialist centre the day the patient is found to have relapsed. More studies need to focus on relapsed ALL but finding donors more rapidly is likely to improve outcome. The Fielding study also shows that allografting (our best antileukaemic therapy) cannot currently be reserved for relapse.

8.  Donor Lymphocyte Infusions Although there is a pronounced GvL effect for ALL, DLI have been relatively ineffective therapy when given for overt relapse of ALL post-allograft [28]. This is likely to be due to the rapid pace of the disease. Kolb and Mackinnon reported the follow-up results of an EBMT study. Only 2 out of 22 patients with relapsed ALL responded to DLI without prior chemotherapy [13]. In an American registry study, 2 of 15 patients obtained CR with DLI. The reported 10% response rate may be due to underreporting of unsuccessful cases and most transplanters do not give DLI as sole therapy for relapse. A recent comprehensive review by Tomblyn and Lazarus describes the data from various small studies [14] and lead the authors to conclude that no firm recommendations can be made on the basis of these (limited) data. However, further studies of DLI after induction chemotherapy or as part of a second transplant strategy are warranted [15]. A more promising pre-emptive approach has been followed by German investigators in paediatric patients. Bader and colleagues showed that in 163 patients, who had allografts from a variety of stem cell sources, the development of mixed chimerism (defined as a >5% shift in whole blood chimerism) was in the absence of intervention associated with universal relapse [16].

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Chimerism was monitored very intensively in their study, weekly in the first year. Their intervention was a program of escalating DLI which resulted in about a third of such patients surviving. Acute GVHD (of some grade) were seen in 31% of such patients. This approach deserves evaluation in an adult population. Some RIC regimens result in a high incidence of mixed chimerism and it is standard practice to correct this mixed chimerism with DLI but there are no data available to assess if this approach reduces relapse.

9.  Allografting for Refractory Disease About 10% of adult patients with ALL are refractory to primary chemotherapy and a very small percentage of these patients can be cured by allogeneic SCT either with a sibling or unrelated donor. Similarly, some patients who relapse fail to respond to reinduction chemotherapy. These patients are often extremely unwell due to prolonged neutropenia and severe infections. The author knows of few such patients who have survived and prefers to attempt to achieve remission with novel agents such as clofarabine, nelarabine or monoclonal antibodies prior to a curative allograft.

10.  Haploidentical and Cord Blood Transplantation for High Risk ALL Patients with ALL, who have a low chance of cure with chemotherapy but have no sibling or suitably matched unrelated donor, are candidates for allografts with haploidentical or cord blood stem cells. The data are small scale and heterogeneous, and come from a small number of centres of excellence. Aversa described 62 patients with ALL transplanted in remission who had 25% event-free survival [17]. TRM was substantial but there was no chronic GVHD, so longer-term quality of life was good. Survival data for patients purely with ALL cannot be gleaned from the reports from Henslee Downey’s group in South Carolina but TRM was seen in 15 of 49 patients and acute and chronic GVHD in about 15%. The data for cord blood transplant is limited. Many studies do not separate this disease from other diseases. Rocha on behalf of Eurocord reported 98 patients (34% in CR1) who achieved 36% 2 year survival and a 26% incidence of grade II–IV acute GVHD and 30% incidence of chronic GVHD [18]. The Minneapolis group have some excellent survival data in small number of adults with ALL but these data cannot be used to make decisions for individual patients. Further larger-scale studies are required, and infection and slow engraftment remain major hurdles.

11.  Other Issues and Supportive Care 11.1.  CNS Disease Patients with CNS disease at diagnosis have an inferior outcome to those without CNS disease (29 vs. 39% survival, p  =  0.03). However, they can achieve long-term DFS with a sibling allograft. In the Lazarus study, 11 of

Chapter 13  Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults 

25 such patients remain alive 21–102 months post-allograft. The issue of whether the dose of cranial radiotherapy that is part of TBI is sufficient for the control of CNS disease remains uncertain. CNS prophylaxis is a major issue for RIC allografting and additional therapy (such as post-transplant intrathecal injections) should be contemplated but there is no evidence to inform practice. 11.2.  Palifermin Grade 4 mucositis is a major problem with VP/TBI allografts with cyclosporin and minidose prophylaxis. Typical patients have severe symptoms requiring prolonged narcotic analgesia and frank bleeding from the mouth. This may prevent the delivery the four doses of methotrexate which, in turn, may affect the chance of acute and chronic GVHD. Some investigators have used mycophenolate mofetil but data showing this to be as effective as methotrexate are lacking. Palifermin (keratinocyte growth factor 1), which has level-one evidence after chemotherapy for autologous SCT has been the subject of phase I studies [19]. 11.3.  The Future Allografting for adults for ALL is currently too toxic and the TRM is too high. Exploration of reduced intensity conditioning in clinical trials will determine whether this is a viable approach and will answer the biologic question of how important conditioning is in obtaining a negative MRD status before the effects of an allogeneic GvL effect. It seems likely that patients with positive MRD prior to transplant and those with resistant disease will not be cured by less conditioning. TBI conditioning may be made less toxic by drugs such as palifermin and velafermin and this may improve the outcome. Selecting the right patients for allogeneic SCT is also a major issue. Gene profiling may add to our abilities to discriminate using the existing prognostic factors. Further trials are needed to determine if allografting can overcome the adverse prognostic impact of biologic factors such as a high WCC and adverse cytogenetics. If allografting can do this, the use of allografting will expand if unrelated donor allografting can be safely performed on a multicentre basis. If it can, then there will be exploration of the use of cord blood as a stem cell source but, again, this is mainly performed in certain specialist centres and there are no data to suggest that it can safely be “rolled out” to large number of transplant centres worldwide (Table 13-4).

Table 13-4.  Likely future developments. • Better selection of patients (who will benefit from allograft) • Increased role for reduced intensity allografting, particularly in older patients • Expanded role for alternative donor allografting including cord blood SCT • Recombinant keratinocyte growth factors to mitigate toxicity of TBI

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D. I. Marks

References 1. Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM (2008) In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/ maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111:1827–1833 2. Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, Vance GH, Cherry AM, Higgins RR, Fielding AK, Foroni L, Paietta E, Tallman MS, Litzow MR, Wiernik PH, Rowe JM, Goldstone AH, Dewald GW, Adult Leukaemia Working Party, Medical Research Council/National Cancer Research Institute (2007) Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): Analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 109:3189–3197 3. Brüggemann M, Raff T, Flohr T, Gökbuget N, Nakao M, Droese J, Lüschen S, Pott C, Ritgen M, Scheuring U, Horst HA, Thiel E, Hoelzer D, Bartram CR, Kneba M, German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (2006) Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 107:1116–1123 4. Passweg JR, Cahn J-Y, Tiberghien P, Vowels MR, Camitta BM, Gale RP, Herzig RH, Hoelzer D, Horowitz MM, Ifrah N, Klein JP, Marks DI, Ramsey NKC, Rowlings PA, Weisdorf DJ, Zhang M-J, Barrett AJ (1998) Graft versus leukaemia effect in T-lineage and cALLa+ (B-lineage) acute lymphoblastic leukaemia. Bone Marrow Transplant 21:153–158 5. Snyder DS, Chao NJ, Amylon MD, Taguchi J, Long GD, Negrin RS, Nademanee AP, O'Donnell MR, Schmidt GM, Stein AS et al (1993) Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission. Blood 82:2920–2928 6. Marks DI, Aversa F, Lazarus H (2006) Alternative donors transplants for adult acute lymphoblastic leukaemia: A comparison of the three major options. Bone Marrow Transplant 38:467–475 7. Frassoni F (2000) Randomised studies in acute myeloid leukaemia: The double truth. Bone Marrow Transplant 25:471–473 8. Kiehl MG, Kraut L, Schwerdtfeger R et al (2004) Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared with unrelated transplant in first complete remission. J Clin Oncol 22:2816–2825 9. Dahlke J, Kröger N, Zabelina T, Ayuk F, Fehse N, Wolschke C, Waschke O, Schieder H, Renges H, Krüger W, Kruell A, Hinke A, Erttmann R, Kabisch H, Zander AR (2006) Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation. Bone Marrow Transplant 37:155–163 10. Mohty M, Labopin M, Tabrizzi R et  al (2008) Reduced intensity conditioning allogeneic stem cell transplantation for adults with acute lymphoblastic leukaemia: A retrospective study of the European BMT group. Haematologica 93:303–306 11. Stein A, O’Donnell M, Parker P, Nademanee A, Falk P, Rosenthal J, Palmer J, Tsai N, Forman S (2007) Reduced-intensity stem cell transplantation for high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant 13:134

Chapter 13  Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults  12. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow M, Buck G, Durrant IJ, Luger SM, Marks DI, McMillan AK, Tallman MS, Rowe JM, Goldstone AH (2006) Outcome of 609 adults after relapse of acute lymphoblastic leukaemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 113:4489–96, 2009 13. Kolb H-J, Mackinnon S (2004) Adoptive cellular immunotherapy for treatment or prevention of relapse of hematologic malignancy posttransplant. In: Atkinson K (ed) Chapter 65 in clinical bone marrow and blood stem cell transplantation, vol 3. Cambridge University Press, New York, pp 992–1008 14. Tomblyn M, Lazarus HM (2008) Donor lymphocyte infusions: The long and winding road: How should it be traveled? Bone Marrow Transplant 42:569–78, 2008 15. Shaw BE, Mufti GJ, Mackinnon S, Cavenagh JD, Pearce RM, Towlson KE, Apperley JF, Chakraverty R, Craddock CF, Kazmi MA, Littlewood TJ, Milligan DW, Pagliuca A, Thomson KJ, Marks DI, Russell NH (2008) Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant 42:783–9, 2008 16. Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P, Kremens B, Dilloo D, Sykora KW, Schrappe M, Niemeyer C, Von Stackelberg A, Gruhn B, Henze G, Greil J, Niethammer D, Dietz K, Beck JF, Klingebiel T (2004) Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22:1696–1705 17. Aversa F (2008) Haploidentical haematopoietic stem cell transplantation for acute leukemia in adults: experience in Europe and the United States. Bone Marrow Transplant 41:473–481 18. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, Jacobsen N, Ruutu T, de Lima M, Finke J, Frassoni F, Gluckman E (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351:2276–2285 19. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, Yanovich S, Hansen K, Noga S, McCarty J, LeMaistre CF, Sung EC, Blazar B R, Elhardt D, Chen MG, Emmanouilides C (2004) Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351:2590–2598 20. Attal M, Blaise D, Marit G, Payen C, Michallet M, Vernant JP, Sauvage C, Troussard X, Nedellec G, Pico J et al (2005) Consolidation treatment of adult acute lymphoblastic leukemia: A prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group. Blood 86:1619–1628 21. Hunault M, Harousseau JL, Delain M, Truchan-Graczyk M, Cahn JY, Witz F, Lamy T, Pignon B, Jouet JP, Garidi R, Caillot D, Berthou C, Guyotat D, Sadoun A, Sotto JJ, Lioure B, Casassus P, Solal-Celigny P, Stalnikiewicz L, Audhuy B, Blanchet O, Baranger L, Béné MC, Ifrah N, GOELAMS (Groupe Ouest-Est des Leucémies Airguës et Maladies du Sang) Group (2004) Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: A GOELAMS trial. Blood 104:3028–3037 22. Marks DI, Pérez WS, He W, Zhang MJ, Bishop MR, Bolwell BJ, Bredeson CN, Copelan EA, Gale RP, Gupta V, Hale GA, Isola LM, Jakubowski AA, Keating A, Klumpp TR, Lazarus HM, Liesveld JL, Maziarz RT, McCarthy PL, Sabloff M, Schiller G, Sierra J, Tallman MS, Waller EK, Wiernik PH, Weisdorf DJ (2008) Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission. Blood 112:426–434

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D. I. Marks 23. Martino R, Giralt S, Caballero MD, Mackinnon S, Corradini P, Fernández-Avilés F et  al (2003) Allogeneic hematopoietic stem cell transplantation with reducedintensity conditioning in acute lymphoblastic leukemia: A feasibility study. Haematologica 88:555–560 24. Massenkeil G, Nagy M, Neuburger S, Tamm I, Lutz C et al (2005) Survival after reduced-intensity conditioning is not inferior to standard high-dose conditioning before allogeneic haematopoietic cell transplantation in acute leukemias. Bone Marrow Transplant 36:683–689 25. Marks DI, Forman SJ, Blume KG, Perez WS, Weisdorf DJ, Keating A, Gale RP, Cairo MS, Copelan EA, Horan JT, Lazarus HM, Litzow MR, McCarthy PL, Schultz KR, Smith DD, Trigg ME, Zhang MJ, Horowitz MM (2006) A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remissi. Biol Blood Marrow Transplant 12:438–453 26. Hamaki T, Kami M, Kanda Y, Yuji K, Inamoto Y, Kishi Y et al (2005) Reduced intensity stem-cell transplantation for acute lymphoblastic leukemia: A retrospective study of 33 patients. Bone Marrow Tranplant 35:549–556 27. Collins RH, Shpilberg O, Drobyski WR et al (2000) Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 15:433–444 28. Horowitz M, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al (1990) Graft versus leukemia reactions after bone marrow transplantation. Blood 75: 555–562 29. Yanada M, Matsuo K, Suzuki T, Naoe T (2006) Allogeneic hematopoietic stem cell transplantation as part of post-remission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: A meta-analysis. Cancer 106:2657–2663 30. Weiden PL, Flournoy N, Thomas ED et  al (1979) Antileukemic effect of graftversus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 300:1068–1073

Chapter 14 Allogeneic Transplantation for Myelodysplastic Syndromes Geoffrey L. Uy and John F. DiPersio

1.  Introduction Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral cytopenias and marrow dysplasia with a variable propensity to evolve into acute myeloid leukemia. MDS is primarily a disease of the elderly with the median age of 76 years at diagnosis and 86% of patients diagnosed over the age of 60 [1]. Although the true incidence is unknown, reports from Germany and the United States estimate the incidence of MDS to be approximately 3 to 4 per 100,000 [1, 2]. While the majority of cases of MDS arise de novo, exposure to alkylating agents and ionizing radiation during treatment for other conditions are important etiological factors. Compared to de  novo MDS, secondary MDS is associated with higher rates of adverse cytogenetics abnormalities, poor treatment response, and a worse overall prognosis [3, 4]. Currently, allogeneic stem cell transplantation is considered the only curable treatment modality for MDS. However, the advanced age and the associated comorbidities typical for this patient population have limited the utility of this approach for most patients.

2.  Classification and Prognostic Factors in MDS The French–American–British classification of 1982, recognizes five distinct subgroups of MDS: (1) refractory anemia (RA), (2) refractory anemia with ringed sideroblasts (RARS), (3) refractory anemia with excess blasts (RAEB), (4) refractory anemia with excess blasts in transformation (RAEB-T), and (5) chronic myelomonocytic leukemia (CMML). These subtypes are based on morphological features in the bone marrow and peripheral blood including the presence of ringed sideroblasts, bone marrow blasts, and peripheral blood monocytes [5].

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_14, © Springer Science + Business Media, LLC 2003, 2010

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Table 14-1.  Comparison of French American British (FAB) and World Health Organization (WHO) classifications of MDS. FAB category

WHO category

Definition

Refractory anemia (RA)

Refractory anemia (RA)

Dysplasia in erythroid series, <5% blasts in marrow and <1% in blood

Refractory anemia with ringed sideroblasts (RARS)

Refractory anemia with ringed sideroblasts (RARS)

Anemia with ³15% erytroid precursors ringed sideroblasts

Refractory anemia with excess blasts (RAEB)

Refractory anemia with excess blasts-1 (RAEB-1)

5–10% myeloblasts in BM

Refractory anemia with excess blasts-2 (RAEB-2)

10–19% myeloblasts in BM

Refractory cytopenia with multilineage dysplasia (RCMD)

Bi- or pancytopenia with dysplastic changes in ³10% of cells in ³2 cell lines

Myelodysplastic syndrome associated with del(5q)

Isolated del(5q) cytogenetic abnormality, <5% blasts in blood and marrow

Myelodysplastic syndrome, unclassifiable (MDS-U)

No increase in blasts in blood and bone marrow, lacks finding appropriate for other categories

Refractory anemia with excess blasts in transformation (RAEB-t) Chronic myelomonocytic leukemia (CMML)

Reclassified from MDS to: Acute myeloid leukemia with multilineage dysplasia

³20% blasts in blood or marrow and dysplasia in ³2 cell lines

Myelodysplastic/myeloproliferative disease Chronic myelomonocytic leukemia (CMML)

<20% blasts in blood or marrow, peripheral blood monocytosis >1×109/L

Recognizing the importance of both bone marrow blast percentage and cytogenetics in MDS, the World Health Organization (WHO) classifi­ cation was devised in 1997 and has largely replaced the previous FAB scheme (Table  14-1). Important distinctions between the FAB and WHO classifications are the placement of CMML into a distinct MDS/MPD overlap subgroup and the lowering of the bone marrow blast percentage for AML to 20% in what was previously classified as RAEB-t. In addition, two additional categories of MDS were added: refractory cytopenias with multilineage dysplasia and MDS associated with an isolated del(5q) chromosome abnormality because of their unique morphologic and clinical characteristics[6]. The natural history of MDS is highly variable. Cytogenetics and the percentage of bone marrow blasts have been recognized as the principal prognostic factors [7]. A number of scoring systems have been developed to stratify the outcomes of patients [8–12]. The most widely adopted of these systems, the International Prognostic Scoring System (IPSS) incorporates cytogenetics, number of cytopenias, and bone marrow blast percentage to stratify patients into low, intermediate, and high risk groups both in terms of overall survival and evolution to AML (Table 14-2) [9].

Chapter 14  Allogeneic Transplantation for Myelodysplastic Syndromes 

205

Table 14-2.  International prognostic scoring system (IPSS) for MDS. Value Prognostic variable

0

0.5

1

1.5

2

BM blasts (%)

<5

5–10

–

11–20

21–30

Poor

a

Good

Intermediate

Cytopenias b

0/1

2/3

Risk group

IPSS score

Median survival (years)

25% AML evolution (years)

Low

0

5.7

9.4

Intermediate-1

0.5–1.0

3.5

3.3

Intermediate-2

1.5–2.5

1.2

1.1

High

>2.5

0.4

0.2

Karyotype

a

Good normal, –Y, del(5q), del(20q), Poor complex (³3 abnormalities) or chromosome 7 anomalies, Intermediate other abnormalities b  Hemoglobin <10 g/dL, absolute neutrophil count <1,800/mm3, or platelet count <100,000/mm3

Table 14-3.  Selected studies of bone marrow transplantation from HLA-matched siblings for MDS. Study

Year

O’Donnell et al. [16] 1987

Median age Median Preparative in years F/U in Patients regimen (range) months DFS

Relapse

TRM

  20

TBI based (75%)

36 (4–48)

35

35%

20%

45%

17

39%

Bu/Cy (25%) Longmore et al. [15]

1990

  23

Various

23 (3–46)

36

43%

Nevill et al. [18]

1992

  23

Bu/Cy

35 (18–55)

27

35% at 22% at 43% at 3 years 3 years 3 years

Sutton et al. [21]

1996

  71

Cy/TBI (37%)

37 (5–55)

72

32% at 78% at 39% at 7 years 7 years 7 years

Bu/Cy (24%) Runde et al. [22]

1998

131

TBI based (70%)

33 (2–55)

27

34% at 39% at 44% at 5 years 5 years 5 years

Sierra et al. [20]

2002

452

TBI based (44%)

38 (2–64)

49

40% at 23% at 37% at 3 years 3 years 3 years

3.  Early Trials of Hematopoietic Stem Cell Transplantation The potential curative role of allogeneic stem cell transplantation (alloSCT) in MDS was established by a series of single institutional studies conducted in the 1980s demonstrating long term disease free survival in patients following bone marrow transplantation from HLA-identical siblings [13–18]. These results have been confirmed by larger registry studies demonstrating 3 year disease free survivals of approximately 35–40% with a TRM of approximately 40% (Table 14-3) [19–23].

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4.  Impact of Age and Disease State Although MDS is primarily a disease of the elderly, until relatively recently alloSCT was rarely offered to individuals over the age of 55. In initial reports of transplantation for MDS, the median age of patients undergoing transplantation was typically between 30 and 40 years. Throughout these major studies, younger age was associated with improved OS due to decreased TRM [19–21, 24, 25]. In the EBMT series, these differences were most pronounced in patients under the age of 20 who had an improved OS (46% for age £ 20 vs. 33% for age > 40, P = 0.05) attributable to lower TRM (25 vs. 57%, P = 0.01) compared to older patients [19]. With improvements in conditioning regimens and supportive care, transplantation has been available to an increasing number of older patients. Deeg et al. reported the results of 50 older patients (55–66 years) undergoing alloSCT for MDS with a 3 year KM estimate of OS of 59% for RA patients and 46% for RAEB patients demonstrating the feasibility of this approach for older patients [26]. Similar to nontransplant studies of MDS, disease morphology and cytogenetics have been identified as important prognostic variables in the outcome of patients undergoing alloSCT. Patients with either low blast percentage (<5%) or RA/RARS subtypes were associated with improved OS post transplant because of a lower risk of relapse. In the IBMTR series, patients with 5–20% blasts at transplantation had a relative risk of relapse of 2.9 (95% CI 1.7–49, P < 0.001) compared those with <5% blasts [20]. In addition, cytogenetic abnormalities had been found to correlate with disease relapse [20, 27, 28]. Not surprisingly, in a study from the Seattle group of 109 patients, the IPSS score correlated with relapse and DFS with the 3 year DFS of 80% for patients with IPSS of 0 decreasing to 29% in those with IPSS > 2 (Fig. 14-1) [29].

5.  Optimal Timing of Transplantation While immediate transplantation is favored for patients with high risk IPSS scores, due to the high risk of transformation to AML and death, the optimal timing of transplantation for patients with lower risk disease is unknown. Retrospective studies have demonstrated that transplantation early in the disease course for MDS has been associated with improved transplant

Fig. 14-1.  Impact of IPSS score on clinical outcome post allogeneic stem cell transplant. From [29]

Chapter 14  Allogeneic Transplantation for Myelodysplastic Syndromes 

outcomes [22, 25] As outcomes are more favorable in patients with low blast counts, transplantation early in their disease course has been advocated prior to disease progression. In addition, earlier transplantation would allow for less alloimmunization and iron overload from blood transfusions. Armand et  al. studied patients with MDS undergoing myeloablative alloSCT and found that an elevated pre-transplantation serum ferritin level in the highest quartile of patients (>2,515  ng/ml) was strongly associated with lower OS and DFS in patients with MDS attributable to a significant increase in TRM (HR = 3.2, P = 0.02) [30]. However, it is difficult to subject younger patients with low or intermediate risk MDS to the risk of morbidity or mortality from stem cell transplantation as these individuals may also have a benign clinical course in the absence of transplantation [9]. To help answer this question, Cutler et  al. constructed a Markov model based on IPSS score to examine 3 transplantation strategies using HLAidentical sibling donors for newly diagnosed MDS: (1) transplantation at diagnosis, (2) transplantation at leukemic progression, or (3) transplantation during a fixed interval from diagnosis prior to progression. For low and int-1 IPSS groups, delayed transplantation maximized overall survival (9.70 (low), 9.68 years (int-1) vs. 5.17, 2.29 years for delayed vs. immediate transplantation) with the greatest differences predicted in the cohort of patients under age 40. For int-2 or high IPSS groups, transplantation at the time of diagnosis maximized overall survival [31]. In addition, no changes in the optimal transplant strategy were seen when adjustments for quality of life measures were incorporated (Fig.  14-2). Supporting this analysis, a report of the German MDS registry of 232 patients, younger than 50 years with MDS, indicates that survival was significantly longer in patients younger than 50 years (40 vs. 23 months, P < 0.005), primarily driven by the outcome of low, and int-1 risk patients with an overall survival rate of 86% at 20 years for low risk and a median survival 176 months for int-1 patients [32]. Although these studies are informative, they do not account for patients who experience life threatening infections or bleeding from their cytopenias and may benefit from early transplantation regardless of their IPSS score.

Fig. 14-2.  Net benefit or loss of overall discounted life expectancy for allogeneic transplantation in IPSS risk group. From [31]

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6.  Role of Induction Chemotherapy Although induction chemotherapy is universally administered in patients with AML prior to alloSCT, its role in MDS is controversial. Because the rate of relapse, post transplant, increases with increasing blast count, the use of induction chemotherapy prior to alloSCT has been attractive as a means to reduce relapse rates. Compared to de novo AML, aggressive antileukemic therapy in MDS results in lower remission rates and for those who fail induction, a poorer outcome following a subsequent allogeneic transplant [33–35]. In addition, induction chemotherapy may delay potentially curative therapy and any toxicities incurred during induction could preclude an individual from subsequent transplantation. The EBMT compared the outcome of unrelated donor transplantation in patients with MDS in CR1 (n = 136) vs. those who are untreated (n = 167). Overall survival at 3 years was superior in patients who were in CR1 (50 vs. 40%, P = 0.01 with improved 3 year DFS (44 vs. 34%, P = 0.03) and lower TRM [36]. Yakoub-Agha in an analysis of treatment related MDS and AML showed that induction chemotherapy before the graft tended to reduce the risk of relapse (HR, 0.44; P = 0.07) without significantly influencing the risk of TRM (HR, 0.60; P = 0.14). Furthermore, EFS and relapse rates were significantly better for patients who achieved CR, compared with those with active disease at transplant (P = 0.02 and P = 0.002), respectively [24]. In contrast, Sutton et  al. examined the role of induction chemotherapy in de novo MDS. They found that induction was associated with a low rate of CR (35%) and did not reduce the rate of relapse even in those achieving a CR and was associated with worse outcomes [21]. Scott et al. presented the Seattle data of 125 patients with MDS and tAML who received transplants from HLA-identical related or unrelated donors after conditioning with myeloablative conditioning regimens and found no benefit in posttransplant outcome associated with prior induction chemotherapy [37]. Due to their retrospective nature, none of these studies can account for patients who may have received induction chemotherapy but did not undergo subsequent transplant because of toxicity or death during induction. Although prospective randomized trials are required to compare the outcome of these two approaches, these trials are unlikely to be performed. With the introduction of the hypomethylating agents, decitabine and 5¢-azacytidine, responses may be seen in up to 40% of patients with minimal toxicity compared to standard antileukemic induction chemotherapy [38–40]. Preliminary data have suggested the feasibility of hypomethylating agents as induction therapy prior to transplant and may be a reasonable approach in symptomatic patients without an HLA-matched sibling in whom an URD transplant may require 3–4 months to coordinate[41].

7.  Donor and Stem Cell Source Approximately 70% of individuals being evaluated for alloSCT do not have a HLA-matched sibling donor and require an unrelated donor (URD) source of stem cells. Anderson et  al. reported on the outcome of 52 patients with MDS or MDS-related AML treated between 1987 and 1993 with unrelated donor marrow transplantation. The 2-year disease-free

Chapter 14  Allogeneic Transplantation for Myelodysplastic Syndromes 

survival, relapse, and non-relapse mortality rates were 38, 28 and 48%, respectively which compares favorably to series using HLA matched sibling donors [42]. The NMDP has reported outcomes of 510 patients with MDS undergoing URD transplant between 1988 and 1998 with a 2 year disease free survival of 26%. Two year incidence of relapse was 14% with 54% 2 year TRM. [43] The EBMT reported 118 patients who underwent alloBMT from URDs between 1986 and 1996 with an actuarial probability of survival at 2 year of 28%, disease-free survival of 28%, relapse risk of 35%, and transplant-related mortality of 58% [44]. Both the NMDP and EMBT indicate improving outcomes associated with transplantation in recent years suggesting that with improvements in HLA-typing and supportive care, the outcomes of fully matched URDs may approach those observed with related donors [19, 43]. More recently, Deeg et  al. reported the outcome of 109 patients with MDS transplanted from both related and unrelated donors who were conditioned with busulfan and cyclophosphamide and found that donor type had no significant impact on outcome [29]. Cytokine mobilized peripheral blood is increasingly used as an alternative stem cell source to bone marrow in alloSCT. Studies in acute and chronic leukemias have consistently demonstrated higher yields of CD34+ stem cells with improved hematopoietic recovery for PBSC compared to that for bone marrow. In several studies, rates of chronic GVHD appears to be increased in individuals receiving PBSCs which has been attributed to a higher T cell dose in the graft while differences in TRM, relapse risk, and OS are more variable [45–49]. Few studies have addressed the differences in stem cell source specifically for patients with MDS. In a retrospective analysis from the EBMT, in addition to faster hematopoietic recovery, the 2-year estimate EFS of 50 vs. 39% ,favored PBSCs due to a reduction in TRM (RR 0.33, 95% CI 0.15–0.73, P < 0.007) in non RA, and high risk cytogenetics patients [50]. In the only major randomized trial to include patients with MDS, 228 patients (36 with MDS) with myeloid malignancies received either G-CSF-mobilized PBSCs or bone marrow from an HLA-matched sibling following Bu/Cy conditioning. PBSC transplantation was associated with a significantly shorter time to engraftment of neutrophils (by 4 days) and platelets (by 6 days) with no difference observed in the rates of acute or chronic GVHD. Overall survival at 30 months was significantly improved for recipients of PBPCs (68 vs. 60 percent, hazard ratio 0.62, 95% CI: 0.39–0.97) due to a reduction in TRM. Although not powered for subgroup analysis, a trend toward improved OS was observed favoring the use of PBSCs for patients with MDS [49]. An recently completed BMT Clinical Trials Network (CTN) trial will help determine the utility of PBSC vs. bone marrow in URDs. For individuals with MDS without an HLA-matched adult donor, use of umbilical cord blood appears to provide a viable alternative [51–55]. Results of transplantation from haploidentical donors in MDS are currently insufficient to warrant its use outside of the context of a clinical trial.

8.  Conditioning Regimens Early studies of alloSCT primarily used Cy/TBI or Bu/Cy based conditioning regimens for allogeneic transplant. Although no direct comparisons have been made, in an analysis of the NMDP data of URD transplants, use of Bu/Cy

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conditioning regimen was associated with improved DFS with a lower incidence of severe acute GVHD and relapse [43]. Favorable outcomes have been observed in the Seattle data in which 109 patients with MDS (median age 46 years) were transplanted using pharmacokinetically targeted Bu/Cy from both HLAmatched and URDs. The nonrelapse mortality for the entire cohort was 31% at 3 years which compares favorably to studies using TBI based conditioning regimens [29]. A major limitation in the use of HSCT in MDS is the high rates of TRM observed using standard TBI or busulfan based conditioning regimens in older patients. Recognizing that the efficacy of alloHSCT is due in part to the immunologic graft vs. disease effect, reduced intensity and nomyeloablative conditioning regimens have become increasingly popular. These regimens attempt to minimize regimen related toxicity while providing enough immunosuppression to allow donor cell engraftment. A number of single arm phase 2 studies in myeloid malignancies have demonstrated the feasibility of this approach using a wide range of conditioning regimens (Table 14-4) [56–61]. Even among RIC regimens, major differences exist in treatment intensity. A comparison of the outcomes of a reduced intensity regimen of fludarabine and melphalan (FM) vs. a truly nonmyeloblative regimen of fludarabine, cytarabine, and idarubicin (FAI) illustrates these potential differences. FM was significantly associated with a higher degree of donor cell engraftment and lower relapse rates (30 vs. 61%) at the expense of higher treatment-related mortality [62]. The EBMT performed a retrospective comparison of RIC with conventional conditioning for alloHCT from HLA identical siblings in MDS. The 3-year probabilities of progression-free and overall survivals were similar in both groups (39% myeloablative vs. 33% in RIC; P = 0.9; and 45 vs. 41%, respectively; P = 0.8). A lower 3-year NRM was observed after RIC group (HR 0.61, 95% CI, 0.41–0.91, P = 0.015) which was encouraging as patients are frequently selected for RIC regimens on the basis of advanced age and comorbid conditions which preclude conventional myeloablative regimens. Supporting this notion, patients receiving RIC were older (age > 50 years in 73% RIC vs. 28%, P < 0.001) and had more adverse pretransplantation variables [63]. The use of RIC has expanded the pool of patients with MDS who are eligible for alloSCT by reducing the high rates of TRM observed with conventional conditioning regimens. These reductions in TRM, however, appear to come at the expense of increased risk of relapse with the optimal strategy to maximize patient outcomes still undefined.

9.  Transplantation of CMML Due to its inclusion as a subtype of MDS under the FAB classification, the outcomes of patients transplanted with CMML have generally been included in larger series of patients with MDS. A few small series have reported the outcome of patients with CMML separately [64–67]. The largest of these series is from the EBMT which reported the results of 50 allogeneic recipients. The 5-year OS was 21% (95% CI: 15–27%) and the 5-years DFS was 18%. Trends were seen favoring transplantation earlier in the disease course for improved DFS. In addition, a trend toward lower relapse rate was observed in patients with acute GVHD and non-T cell depleted grafts suggesting a graft vs. CMML effect [66].

2006

2004

2005

2003

2007

Hallemeier et al. [56]

Ho et al. [57]

Tauro et al. [58]

Maris et al. [61]

van Besien et al. [59]

52 (11)

89 (21)

76 (20)

62 (39)

51 (51)

CSA (+MTX in URD) CSA

CSA

CSA and MMF FK506

Flu (150 mg/m2), Busulfan, Alemtuzumab (100 mg)

Flu (150 mg/m2), Mel (140 mg/m2), Alemtuzumab (100 mg)

Flu (90 mg/m2), TBI (200 cGy)

Flu (150 mg/m2), Mel (140 mg/m2), Alemtuzumab (100 mg)

GVHD prophylaxis

Cy, TBI (550 cGy)

Preparative regimen

For MDS/MPD subgroup only

a

Flu fludarabine, TBI total body irradiation, Cy cyclophosphamide, mel melphalan

Year

Study

Patients (# with MDS)

52 (17–71)

53

52 (18–71)

53 (22–70)

44 (19–70)

Median age in years (range)

18

13

36

12

46

Median F/U in months

38% at 1 year

25% at 1 yeara

37% at 3 years

62% at 1 year

37%

PFS

Table 14-4.  Selected studies of reduced intensity and nonmyeloablative preparative regimens in MDS.

32%

NR

36%

NR

27%

Relapse

33% at 1 year

17%

19% at 1 year

15% at 1 year

37%

TRM

48% at 1 year

29% at 1 yeara

41% at 3 years

74% at 1 year

OS

Chapter 14  Allogeneic Transplantation for Myelodysplastic Syndromes  211

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10.  Transplantation of JMML Juvenile myelomonocytic leukemia is a rare hematopoietic disorder of early childhood characterized by proliferation of granulocytic and monocytic lineages with frequent erythroid and megakaryocytic abnormalities. JMML accounts for 2–3% of all pediatric leukemias, responds poorly to chemotherapy and can be rapidly fatal [68–72]. While allogeneic transplantation is considered the only curative treatment, published studies report limited number of patients with heterogeneous approaches [73–82]. The largest prospective trial for JMML was conducted by the European Working Group on Childhood MDS and the EBMT which treated 100 patients with alloHCT following conditioning with busulfan, cyclophosphamide, and melphalan. The 5-year EFS was 52% with the KM estimate of OS of 64% with a 13% TRM. Multivariate analysis showed that female sex and age > 4 years at diagnosis predicted for poorer outcomes [83].

11.  Conclusions Allogeneic stem cell transplantation is a potentially curative treatment option for patients with MDS. Patients at high risk for death and disease progression to AML based on IPSS score with high percentage of marrow blasts and adverse cytogenetic abnormalities should be transplanted early in their disease course. For patients who are transfusion independent with low risk disease, transplantation may be deferred until disease progression. Although controversial, either conventional antileukemic induction chemotherapy or the hypomethylating agents, decitabine and 5-azacytidine, may be considered prior to transplantation in patients with high marrow blasts percentages especially if there will be a significant delay until transplantation due to donor availability. Reduced intensity and nonmyeloablative treatment approaches have increased the number of patients who are eligible for transplantation with reduced rates of TRM at the expense of an increased relapse risk with no differences in overall survival.

References   1. Ma X et  al (2007) Myelodysplastic syndromes: Incidence and survival in the United States. Cancer 109(8):1536–1542   2. Aul C, Gattermann N, Schneider W (1992) Age-related incidence and other epidemiological aspects of myelodysplastic syndromes. Br J Haematol 82(2):358–367   3. Estey EH (1998) Prognosis and therapy of secondary myelodysplastic syndromes. Haematologica 83(6):543–549   4. Kantarjian HM et  al (1986) Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features. J Clin Oncol 4(12):1748– 1757   5. Bennett JM et  al (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51(2):189–199   6. Jaffe E et al (2001) World health organization classification of tumours: Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, France   7. Jacobs RH et al (1986) Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. Blood 67(6):1765–1772

Chapter 14  Allogeneic Transplantation for Myelodysplastic Syndromes  8. Aul C et  al (1992) Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 6(1):52–59 9. Greenberg P et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89(6):2079–2088 10. Malcovati L et al (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25(23):3503–3510 11. Mufti GJ et al (1985) Myelodysplastic syndromes: A scoring system with prognostic significance. Br J Haematol 59(3):425–433 12. Sanz GF et al (1989) Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: A multivariate analysis of prognostic factors in 370 patients. Blood 74(1):395–408 13. Appelbaum FR et  al (1987) Treatment of preleukemic syndromes with marrow transplantation. Blood 69(1):92–96 14. Belanger R et  al (1988) Bone marrow transplantation for myelodysplastic syndromes. Br J Haematol 69(1):29–33 15. Longmore G et  al (1990) Bone marrow transplantation for myelodysplasia and secondary acute nonlymphoblastic leukemia. J Clin Oncol 8(10):1707–1714 16. O'Donnell MR et al (1987) Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes. J Clin Oncol 5(11):1822–1826 17. Ratanatharathorn V et  al (1993) Busulfan-based regimens and allogeneic bone marrow transplantation in patients with myelodysplastic syndromes. Blood 81(8):2194–2199 18. Nevill TJ et  al (1992) Treatment of myelodysplastic syndrome with busulfancyclophosphamide conditioning followed by allogeneic BMT. Bone Marrow Transplant 10(5):445–450 19. de Witte T et al (2000) Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantati. Br J Haematol 110(3):620–630 20. Sierra J et al (2002) Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100(6):1997–2004 21. Sutton L et  al (1996) Factors influencing outcome in de  novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: A long-term study of 71 patients Societe Francaise de Greffe de Moelle. Blood 88(1):358–365 22. Runde V et al (1998) Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: Early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 21(3):255–261 23. Ratanatharathorn V et al (1992) Allogeneic bone marrow transplantation in highrisk myeloid disorders using busulfan, cytosine arabinoside and cyclophosphamide (BAC). Bone Marrow Transplant 9(1):49–55 24. Yakoub-Agha I et al (2000) Allogeneic bone marrow transplantation for therapyrelated myelodysplastic syndrome and acute myeloid leukemia: A long-term study of 70 patients-report of the French society of bone marrow transplantation. J Clin Oncol 18(5):963–971 25. Anderson JE et al (1993) Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome. Blood 82(2):677–681 26. Deeg HJ et al (2000) Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95(4):1188–1194 27. Nevill TJ et  al (1998) Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation. Blood 92(6):1910–1917

213

214 

G.L. Uy and J.F. DiPersio 28. Appelbaum FR et  al (1990) Bone marrow transplantation for patients with myelodysplasia. Pretreatment variables and outcome. Ann Intern Med 112(8):590–597 29. Deeg HJ et al (2002) Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 100(4):1201–1207 30. Armand P et  al (2007) Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 109(10):4586–4588 31. Cutler CS et al (2004) A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104(2):579–585 32. Kuendgen A et  al (2006) Myelodysplastic syndromes in patients younger than age 50. J Clin Oncol 24(34):5358–5365 33. De Witte T et al (1989) Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndromes. Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG). Bone Marrow Transplant 4(Suppl 3): 38–39 34. de Witte T et al (1995) Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG). Leukemia 9(11):1805–1811 35. Ruutu T et al (1997) Intensive chemotherapy of poor prognosis myelodysplastic syndromes (MDS) and acute myeloid leukemia following MDS with idarubicin and cytarabine. Leuk Res 21(2):133–138 36. Al-Ali HK et al (2007) A retrospective comparison of autologous and unrelated donor hematopoietic cell transplantation in myelodysplastic syndrome and secondary acute myeloid leukemia: a report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Leukemia 21(9):1945–1951 37. Scott BL et  al (2005) Pretransplantation induction chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic syndrome. Biol Blood Marrow Transplant 11(1):65–73 38. Kantarjian H et al (2007) Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109(1):52–57 39. Silverman LR et al (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20(10):2429–2440 40. Wijermans P et al (2000) Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: A multicenter phase II study in elderly patients. J Clin Oncol 18(5):956–962 41. McCarty J (2004) Transplant strategies for myelodysplastic syndrome. Best Pract Res Clin Haematol 17(4):559–572 42. Anderson JE et  al (1996) Unrelated donor marrow transplantation for myelodysplasia (MDS) and MDS-related acute myeloid leukaemia. Br J Haematol 93(1):59–67 43. Castro-Malaspina H et  al (2002) Unrelated donor marrow transplantation for myelodysplastic syndromes: Outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 99(6):1943–1951 44. Arnold R et al (1998) Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: An EBMT survey. European Blood and Marrow Transplantation Group. Bone Marrow Transplant 21(12):1213–1216

Chapter 14  Allogeneic Transplantation for Myelodysplastic Syndromes  45. Schmitz N et  al (2002) Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia. Blood 100(3):761–767 46. Gorin NC et al (2003) Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow. Blood 102(8):3043–3051 47. Stem Cell Trialists' Collaborative Group (2005) Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: An individual patient data meta-analysis of nine randomized trials. J Clin Oncol 23(22):5074–5087 48. Remberger M et  al (2005) Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Blood 105(2):548–551 49. Couban S et  al (2002) A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 100(5):1525–1531 50. Guardiola P et  al (2002) Retrospective comparison of bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic syndromes. Blood 99(12):4370–4378 51. Brunstein CG et  al (2007) Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood 110(8):3064–3070 52. Ooi J et  al (2003) Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 101(12):4711–4713 53. Ooi J et al (2001) Unrelated cord blood transplantation for adult patients with myelodysplastic syndrome-related secondary acute myeloid leukaemia. Br J Haematol 114(4):834–836 54. Ooi J et al (2005) Unrelated cord blood transplantation after myeloablative conditioning for adult patients with refractory anemia. Int J Hematol 81(5):424–427 55. Picardi A et al (2004) Unrelated cord blood transplantation for children with high risk myelodysplastic syndromes. Haematologica 89(5):ELT08 56. Hallemeier CL et al (2006) Long-term remissions in patients with myelodysplastic syndrome and secondary acute myelogenous leukemia undergoing allogeneic transplantation following a reduced intensity conditioning regimen of 550 cGy total body irradiation and cyclophos. Biol Blood Marrow Transplant 12(7):749–757 57. Ho AY et  al (2004) Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood 104(6):1616–1623 58. Tauro S et al (2005) Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and longterm disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 23(36):9387–9393 59. van Besien K et al (2005) Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23(24):5728–5738 60. Parker JE et al (2002) Allogeneic stem cell transplantation in the myelodysplastic syndromes: Interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens. Br J Haematol 119(1):144–154 61. Maris MB et  al (2003) HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102(6):2021–2030 62. de Lima M et  al (2004) Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic

215

216 

G.L. Uy and J.F. DiPersio syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplant. Blood 104(3):865–872 63. Martino R et al (2006) Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 108(3):836–846 64. Elliott MA et  al (2006) Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia. Bone Marrow Transplant 37(11):1003–1008 65. Kerbauy DM et al (2005) Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia. Biol Blood Marrow Transplant 11(9):713–720 66. Kroger N et al (2002) Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 118(1):67–73 67. Zang DY et al (2000) Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation. Br J Haematol 110(1):217–222 68. Chan HS et al (1987) The value of intensive combination chemotherapy for juvenile chronic myelogenous leukemia. J Clin Oncol 5(12):1960–1967 69. Hasle H et  al (1996) Intensive chemotherapy in childhood myelodysplastic syndrome. A comparison with results in acute myeloid leukemia. Leukemia 10(8):1269–1273 70. Niemeyer CM et  al (1997) Chronic myelomonocytic leukemia in childhood: A retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 89(10):3534–3543 71. Woods WG et al (2002) Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: A report from the Children’s Cancer Group. J Clin Oncol 20(2):434–440 72. Korthof ET et al (2005) Allogeneic bone marrow transplantation for juvenile myelomonocytic leukemia: A single center experience of 23 patients. Bone Marrow Transplant 35(5):455–461 73. Bunin NJ et  al (1992) Allogeneic marrow transplantation using T cell depletion for patients with juvenile chronic myelogenous leukemia without HLA-identical siblings. Bone Marrow Transplant 9(2):119–122 74. Chown SR et al (1996) Matched and mismatched unrelated donor bone marrow transplantation for juvenile chronic myeloid leukaemia. Br J Haematol 93(3): 674–676 75. Donadieu J et al (1994) Treatment of juvenile chronic myelomonocytic leukemia by allogeneic bone marrow transplantation. Bone Marrow Transplant 13(6):777–782 76. Locatelli F et al (1996) Role of allogeneic bone marrow transplantation from an HLA-identical sibling or a matched unrelated donor in the treatment of children with juvenile chronic myeloid leukaemia. Br J Haematol 92(1):49–54 77. Locatelli F et al (1997) Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: A report from the European Working Group on Myelodysplastic Syndrome in Childhood. J Clin Oncol 15(2):566–573 78. MacMillan ML et  al (1998) Haemopoietic cell transplantation in children with juvenile myelomonocytic leukaemia. Br J Haematol 103(2):552–558 79. Matthes-Martin S et al (2000) Allogeneic bone marrow transplantation for juvenile myelomonocytic leukaemia: A single centre experience and review of the literature. Bone Marrow Transplant 26(4):377–382 80. Sanders JE et al (1988) Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia. Blood 71(4):1144–1146 81. Smith FO et al (2002) Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 116(3):716–724

Chapter 14  Allogeneic Transplantation for Myelodysplastic Syndromes  82. Yusuf U et  al (2004) Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: The Seattle experience. Bone Marrow Transplant 33(8):805–814 83. Locatelli F et al (2005) Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): Results of the EWOGMDS/EBMT trial. Blood 105(1):410–419

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Chapter 15 Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia Adriana Balduzzi, Lucia Di Maio, Mary Eapen, and Vanderson Rocha

1.  Introduction Acute lymphoblastic leukemia (ALL) is the most common neoplastic disease in childhood with an incidence of four new diagnoses per year out of 100,000 children below 18 years of age [1–3]. Almost 40  years have passed since the first reports that childhood ALL was no longer incurable [4]. Its prognosis significantly improved over the last decades and important lessons about curing acute leukemia have been learned. The improved outcome of pediatric ALL is one of the greatest successes in modern medicine, with the cure rate having improved from 3% in the 1960s to 80% currently in developed countries [5]. Intensity of induction, rotational polychemotherapy, central nervous system directed treatment additional intensification and maintenance chemotherapy have led to remarkable improvements, despite the fact that the drugs available have not substantially changed over the last 50 years. Very early on, uniform therapy for all patients was replaced in the German Berlin-Frankfurt Munster (BFM) and the United States Clinical Oncology Group (COG) protocols in favor of treatment tailored to prognostic factors, which has allowed for the continued improvements in treatment outcome. These advances are the result of basic research, biologic investigations, large clinical trials and intensive collaboration of cooperative groups [6–8]. The COG recently reported event-free survival (EFS) rates in excess of 90% for standard risk patients defined as age less than 10 years at diagnosis and white blood cell count (WBC) count under 50 × 109/L. Overall, about three quarters of the affected children, at least in developed countries, should now achieve long-term remission and cure after front-line therapy. Unfortunately, the remaining 25% of children relapse despite appropriate treatment, leukemia relapse being the commonest cause of treatment failure [10].

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_15, © Springer Science + Business Media, LLC 2003, 2010

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1.1.  Transplantation: Where Are We Now? Indications for allogeneic hematopoietic stem cell transplantation (HSCT) for childhood ALL has evolved over time due to improvements in treatment outcome with chemotherapeutic regimens as well as better understanding of risk factors, including novel ways to detect minimal residual leukemia and the intensity of therapy tailored to the risk status of a given patient. Transplantation is recommended for only a minority of patients at presentation, commonly defined as “very high risk” (VHR) or “ultra high risk” (UHR) and for the majority of those who experience relapse. Eligibility criteria for HSCT vary according to different chemotherapy protocols; most current protocols identify about 10% of all childhood ALL population presenting with dismal prognostic factors [11]. Much of the philosophy of looking at prognostic factors in childhood leukemia has been aimed at reducing the intensity of therapy in children with low risk ALL and intensifying therapy in those at VHR [12]. For the relatively few VHR patients, only through international collaborations can the relevant therapeutic questions be asked in the context of randomized clinical trials [13]. Pediatric hematologists are now in the difficult position of identifying subsets of patients in whom the intensity of treatment can be lowered to reduce toxicity, and the patient groups who may benefit from intensifying current regimens to improve EFS [13]. HSCT is often used for children with ALL who fail conventional chemotherapy. Crucial roles in transplantation are played by the myeloablative effect of the conditioning regimen and the alloreactivity of donor cells, potentially eradicating residual leukemic cells in the patient. Defining the appropriate use of transplantation is a dynamic process, requiring constant assessment of the likelihood of cure with chemotherapy only, in order to identify the subsets of children who would benefit from transplantation. The role of HSCT is also influenced by changes in the technique of transplantation, mostly the increased availability of unrelated donors worldwide, the higher resolution of HLA typing, allowing better donor–recipient matching and, therefore, improved results and the encouraging results, of other alternative donors such as umbilical cord blood or fully haploidentical HSCT [14–17]. Though improved management of infection and graft-versus-host disease (GvHD) in the current era lessens the risk, death from HSCT-related complications remains higher than with chemotherapy alone. However, disease control appears to be superior after successful transplantation. There is a critical need for an international consensus on identifying those at greatest risk of recurrent disease who consequently benefit from HSCT and conversely those who are less likely to experience leukemia recurrence and for whom chemotherapy alone will achieve long-term cure [11, 15]. Randomized controlled clinical trials have progressively become the gold standard by which treatment choices are made. Each patient is randomized between a new treatment and the perceived standard treatment at trial design and initiation. Oncology, especially pediatric oncology, has par excellence been one of the specialties that have adopted the approach of randomized controlled trials. Faith in such an approach has been reinforced by the unique evidence in children in whom the outcome has been influenced by participation in trials. Even in hands of experienced physicians, it appears that following a protocol,

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

including treatment and supportive care, benefits the patient, regardless of the randomization question [13]. In fact, the question surrounding randomization of one treatment option versus another in a trial may not be the most important lesson learnt. The randomization between two doses of the same drug or two drugs may show no relevant differences, but often EFS and survival are superior to previous trials, implying systematic and consistent treatment also play an important role [13]. Nevertheless, to date, the evidence upon which a decision is made to transplant a child with ALL, either in first or in a subsequent remission, has rarely been based on data from randomized trials [13]. In the absence of randomized trials addressing the role of HSCT, there is reliance on data collected by observational databases (e.g., European Blood and Marrow Transplant group [EBMT]) to identify the role of HSCT [16]. Consequently, the co-operatives groups in several countries have established transplantation guidelines for frontline and relapse protocols, based on retrospective comparisons of treatment options (chemotherapy vs. HSCT). Seldom is the decision to offer transplantation at the discretion of the transplant center, often driven by the availability of a suitable donor [16]. In the last decade, results of allogeneic HSCT from unrelated donors has improved to the extent that there is increasing agreement that outcomes after related and matched unrelated donor HSCT in pediatric ALL are comparable [17]. Nevertheless, there is no demonstration that equipoise exists between the two treatments. As such, unrelated donor search activation and transplantation are not recommended for every child for whom an allogeneic transplantation is indicated. Disparities within donor and recipient pairs are progressively accepted as the risk profile of the patient worsens [18]. According to the concepts of the German-BFM, International-BFM (I-BFM) and the EBMT, pediatric patients with high risk frontline or relapsed ALL require additional strategies after polychemotherapy; HSCT shows promising results mainly due to the conditioning regimen and an immunological control by the graft-versus leukemia (GvL) effect, but transplant-related mortality remains an issue. To investigate the role of transplantation the I-BFM Study Group initiated a multicenter, controlled, prospective study enrolling all patients with ALL in first, second, or subsequent remission, at high risk of relapse defined by cytogenetics, biological characteristics, response to chemotherapy, time and site of relapse. The main objective of the study is to investigate whether transplant from a closely HLA-matched unrelated donor is equivalent to transplant from HLA-identical sibling donors [19].

2.  Prognostic Factors in Pediatric Acute Lymphoblastic Leukemia Some children can be identified at diagnosis as being at a higher risk of relapse. The early identification of prognostic variables allow for tailored treatment such that children who are expected to have a very good outcome with modest therapy can be spared the more intensive and toxic treatment, whereas a more aggressive and thus more toxic, therapeutic approach, particularly HSCT, can be offered to those who have a lower probability of long-term survival with conventional therapy [20].

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Childhood ALL is a heterogeneous group of disorders, differing for only partially known molecular genetic abnormalities which lead to different clinical behavior. A number of clinical and laboratory features have demonstrated prognostic value and can be grouped in the following categories: · clinical and laboratory features at diagnosis: age, WBC count, extramedullary involvement · leukemic cell characteristics at diagnosis: morphology, immunophenotype, cytogenetic · response to initial treatment: clearance of leukemic cells in the peripheral blood (PB) or in the bone marrow (BM) (PB response to the 7-day steroid pro-phase, BM response at day 7 and 14, PB response to multiagent induction therapy, minimal residual disease (MRD) after 1- or 2-month induction chemotherapy). The treatment itself is regarded as the most important prognostic factor and consequently all other prognostic factors are treatment dependent. Therefore improvements in therapy may decrease or delete the significance of any of these presumed biologic prognostic factors. 2.1.  Clinical and Laboratory Features at Diagnosis 2.1.1.  Age Young children between 2 and 10 years of age have a better EFS than older children, adolescents, or infants, which is only partially explained by the more frequent occurrence of favorable cytogenetic features in leukemic blasts, hyperdiploidy or TEL-AML1 translocation and the less frequent occurrence of unfavorable features such as the MLL rearrangement (present in 80% of infants) or BCR/ABL translocations (present in 30% of adults) [21–23]. Infants with ALL have a particularly poor outcome, especially if they are younger than 6  months. Infants often present with a very high WBC count, CNS involvement and MLL gene rearrangement [24, 25]. Infant ALL blasts are typically CD10/cALLa negative, express myeloid antigens, high levels of FLT3 and show poor response to the prednisone prophase [26, 27]. The decision to offer HSCT as front-line therapy may be controversial, given these patients are subject to early toxicity from the chemotherapeutic regimen and HSCT and late effects after transplantation can be particularly severe. Induction failure, treatment-related mortality, higher rates of CNS relapse and early overall failure are common in infants with ALL. Overall 5-year EFS rates range between 25% and 40% in those who respond to steroids, as defined by the BFM. In the BFM 1986 study, 19 infants with good steroid response, defined as having less than 1,000 blasts/mm3 in peripheral blood after 7 days of steroids, reported EFS of 53%, compared with EFS of 14% in the 14 patients with poor steroid response. The importance of early response to steroids resulted in change of practice. HSCT as front-line therapy is not offered to infants who are good steroid responders in order to spare them from the higher early toxicity and long-term morbidity and mortality associated with the procedure [11]. Between 1999 and 2005, 22 European and American countries enrolled 482 infants with ALL on the Interfant-99 Protocol. The aims of this international collaboration were to assess the outcome of a hybrid treatment, based on high

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

risk BFM-like ALL protocols containing elements usually designed for AML, without irradiation, limited doses of anthracycline and alkylating agents, and to assess the impact of adding a late intensification course. The addition of the late intensification course was the randomized component of the trial. In Interfant-99, response to prednisone was the sole criteria for stratification and HSCT was recommended only for poor steroid responders. In the group of patients who were poor steroid responders, EFS rates in HSCT recipients and nonrecipients were similar after adjustment for time to transplant from remission [28]. The extremely good outcome (4-year EFS of 74%) in infants with germlineMLL has limited HSCT to infants with the MLL rearrangement (recorded in 89% of those for whom the MLL status was known), for whom an overall outcome of approximately 37% was reported, even though improved compared to previous reports [21, 25, 29]. Similarly a dismal prognosis was reported for infants 6-month-old or younger (4-year EFS 34%), with WBC counts 300 × 109/L or higher (4-year EFS 26%), and experiencing a poor response to prednisone prophase (4-year EFS 30%) [28]. The new international collaborative treatment protocol Interfant-06, for infants with ALL or biphenotipic leukemia, is ongoing. Infants presenting without MLL rearrangement are stratified as low risk; infants 6  months or younger presenting with MLL rearrangement and WBC ³300 × 109/L at the onset and/or poor prednisone response are considered high risk; all others are stratified as medium risk. HSCT using a matched related or unrelated donor is recommended to only those considered high risk and those achieving CR. Conditioning regimens consisting of chemotherapy only are indicated for infants, who should always be spared TBI. Busulfan is an established myeloablative alternative to TBI which has shown good results in AML. The recommended conditioning regimen for infants consists of busulfan (total dose 20 mg/kg; 1.25 mg/kg/dose at 6-h intervals for 4 consecutive days), cyclophosphamide (total dose 120 mg/kg; 60 mg/kg/dose per day for 2 consecutive days) and melphalan (140 mg/m2, single dose) [19]. Given the variability in absorption associated with oral administration of busulfan, monitoring blood levels has allowed for optimization of efficacy while reducing toxicity. Parenteral busulfan became available in the last decade. This has overcome problems with bioavailability, the discomfort of oral intake, and, in many cases, the placement of a feeding tube for busulfan administration. Among children, infants experience the worst sequelae in terms of growth after HSCT [25]. Tomizawa described growth-impairment in 59% of the MLL-rearranged group, with a highest incidence of transplant-related mortality [30]. 2.1.2.  Hyperleukocytosis Higher WBC counts represent an increased risk for treatment failure in patients with precursor-B ALL. WBC counts of 50 × 109/L in the United States and 100 × 109/L in Europe are adopted as operational cut-points between better and poorer prognosis strata, although the relationship between WBC count and prognosis is a continuous rather than a step function. Most current ­protocols do not consider WBC counts per se as a criterion for transplantation [20]. The National Cancer Institute (NCI)-risk classified ALL at initial presentation

223

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as standard-risk if age was 1–9 years and WBC count <50,000/ml, and high risk all others. 2.1.3.  Extramedullary Involvement Children with extramedullary disease at diagnosis, mostly in the CNS, occurring in approximately 10% of the childhood ALL population, are at higher risk of relapse, both within the CNS and systemically. Specific therapy directed at the involved extramedullary sites is part of current protocols. With more aggressive initial therapy, the prognostic significance of extramedullary involvement may be overcome. Involvement of the CNS at diagnosis per se is not an indication for transplantation in first complete remission, though an isolated CNS relapse is considered by some as an indication for HSCT (see indications in second CR). 2.1.4.  Down Syndrome Outcome for Down syndrome (DS) children with ALL, almost invariably characterized by B-cell precursor phenotype, and often TEL/AML1 negative, is generally inferior to children without DS [31]. DS per se is not an indication for HSCT. The lower EFS and overall survival (OS) in DS appear to be related to higher rates of treatment-related mortality (TRM), especially during induction therapy, and the absence of favorable biological features [32, 33]. The Children’s Cancer Group (CCG) reported significantly lower 10-year EFS (56% vs. 74%, p < 0.001) for 179 standard risk ALL patients with DS compared to 8,268 children without DS, despite similar prognostic factors in the two populations [34]. Among high risk DS and non-DS patients, EFS rates were similar suggesting intensification is beneficial for DS patients [34]. The Medical Research Council – United Kingdom ALL working party (MRC UKALL WP) – observed lower EFS in DS patients; treatment-related mortality rates were very high, regardless of stratification, and intensification of therapy in these patients may not always be feasible [35]. The Italian AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) compared treatment outcomes in 120 patients with DS and 6,237 non-DS patients treated between 1982 and 2004. Induction death and leukemia relapse occurred more often than in the non-DS population and 10-year EFS was worse in the DS group but this improved overtime allowing 75% to survive [31]. 2.2.  Leukemic Cell Characteristics at Diagnosis 2.2.1.  Morphology The French-American-British (FAB) morphology classification is not associated with treatment outcome. 2.2.2.  Immunophenotype Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR and other B-associated antigens, represents 85% of childhood ALL. Approximately 80% of them express CD10 (cALLa) and have the best prognosis [36]. Two percent of the patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and c-MYC gene translocation)

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

also called Burkitt-leukemia, which is a systemic manifestation of Burkitt-like non-Hodgkin lymphoma and should be treated accordingly. This is no longer considered as high risk leukemia. Use of short-term intensive protocols such as those used for B-lymphoblastic lymphoma of childhood achieve EFS of 85%, at least in patients who are t(8;14) (q24;q32) negative after the first chemotherapy cycle [37]. Patients with persistent t(8;14) (q24;q32) positivity may benefit from treatment with anti-CD20 monoclonal antibody and the role of HSCT unclear [38]. Approximately 15% of childhood ALL are precursor T, as defined by the expression of T-cell-associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5). Precursor T-ALL is frequently associated with a constellation of clinical features, including male gender, older age, hyperleukocytosis and mediastinal mass. With appropriate intensive therapy, children with T-ALL have outcomes similar to that of children with B-lineage ALL. Recently, Schrauder reported overall 5-year EFS of 51% in 576 patients with T-ALL; 191 of these children had other VHR features which made them eligible for transplantation from a compatible related donor. Thirty-six of 191 underwent HSCT, 26 from an identical sibling and 13 from an alternative donor (8 unrelated and 5 haploidentical). Five-year DFS in the 191 VHR children with T-ALL were 42% after chemotherapy alone, 65% after HLAidentical sibling transplant and 69% after alternative donor transplant [39]. 2.2.3.  Cytogenetics The t(9;22) translocation is present in approximately 3–4% of children with ALL and commoner in older patients and/or those presenting with hyperleukocytosis. The t(9;22), detected either as Philadelphia chromosome at conventional cytogenetics or as BCR/ABL transcript at molecular analysis, confers unfavorable prognosis, especially when associated with either a high WBC count or slow early response to initial therapy [40]. Aricò reported 5-year disease-free survival (DFS) of 25% after chemotherapy alone and 65% after transplantation in 267 of 326 patients achieving CR1 and treated between 1986 and 1996 (recruited by investigators participating in the Ponte di Legno Group, a working group established in 1995 by the AIEOP, BFM, COG and St. Jude Research Hospital) [41]. Forty-two children with t(9;22) were enrolled in the UKALL trials between 1997 and 2002; 28 underwent HSCT. Three-year DFS was 52% after chemotherapy, 45% after HLA-identical sibling transplant and 68% after unrelated donor transplant [42]. In the prospective international study reported by Balduzzi, of the 83 patients presenting with t(9;22), 23 of the 75 patients in the no donor arm were alive in CCR (continuous complete remission) (DFS 26%) versus 4 of the 8 patients in the group with a donor available for HSCT. Of the 75 patients without a donor, 11 were also poor responders to prednisone and none of these patients were alive in CCR [43]. Talano reported a series of 29 children with t(9;22) who underwent transplantation from non-HLA-identical sibling donors with 65% of 5-year DFS [44]. Whether the addition of imatinib or other tyrosine kinase inhibitors to chemotherapy regimens prior to transplantation can further improve DFS is being investigated. Rearrangements involving the MLL (11q23) gene occur in approximately 2–5% of childhood ALL and are associated with increased risk for treatment

225

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failure [21, 25]. The t(4;11) is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases (see above) and is an indication for HSCT [29, 45]. 2.3.  Response to Initial Treatment Speed of response is increasingly emerging as the single most important treatment-related prognostic characteristic [46]. Various ways of evaluating the leukemia cell response to treatment have been utilized. · Prednisone poor response (PPR). Very early response after the first week of treatment is defined by peripheral blood response to steroid prophase, in protocols that adopt the steroid prophase, or by bone marrow or peripheral blood response after the weeks 1–2 of multiagent induction therapy. PPR is defined as the presence of 1 × 109 blasts/L or higher in peripheral blood after 7 days of prednisone monotherapy and a single dose of intrathecal methotrexate, as first described within the BFM. Its is presence per se defines patients as high risk for whom and intensified chemotherapy is planned, within BFM-based protocols. When associated with other high risk features, that is, hyperleukocytosis, age younger than 1 year, t(9;22) and T-immunophenotype these patients are defined as VHR. Aricò reported 4-year EFS of 57% in 198 PPR patients enrolled in the AIEOP trial, 176 of whom proceeded with chemotherapy alone and 22 with transplantation (15 from HLA-identical siblings and 12 from an unrelated donor) [47]. PPR per se was not considered an indication for transplantation, unless it was associated with hyperleukocytosis (WBC>100 × 106/L at the onset) or T-immunophenotype. The above criteria no longer hold unless associated with slow response to induction as defined by molecular analysis. · Early multidrug response. In the United States, the CCG and the Pediatric Oncology Group (POG) joined to form the Children’s Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic and early response data predictive of EFS in ALL to develop a new classification system and treatment algorithm [9, 36]. Augmented treatment was adopted for high risk and standard risk patients with bone marrow blast count ³25% on day 14. Both standard and high risk patients with a slow early response to prednisone had a 10 point lower 5-year EFS compared to the rapid responders for the day-7 criterion and an 18 point lower 5-year EFS for the day-14 criterion [36]. · Minimal residual disease after induction therapy. In the last decade detection of minimal residual disease (MRD) turned out to be the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood ALL, to the extent that it overcame most “biological” high risk features, which decrease their predictive value when MRD is included into survival analysis models [9, 48, 49]. The detection by PCR of leukemia-associated clonal rearrangements of T-cell receptor and immunoglobulin heavy chain genes at particular phases of treatment beyond induction is linked to poor prognosis.

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

MRD diagnostics using RQ-PCR analysis of immunoglobulin/T-cell receptor gene rearrangements is feasible in multicenter studies but requires standardization and strict guidelines for interpretation of RQ-PCR data along with regular laboratory quality controls. The European Study Group on MRD detection in ALL (ESG-MRD-ALL), consisting of 30 MRD-PCR laboratories worldwide, has developed guidelines for the interpretation of real-time quantitative PCR-based MRD data [50, 51]. Between 2000 and 2004, 3341 patients were enrolled in the multicenter trial AIEOP-BFM ALL 2000 (closed in 2006). They were stratified by MRD detection using quantitative PCR after induction (time point 1) and consolidation treatment (time point 2). MRD-based risk group assignment was feasible in 78% of the patients: 40% were classified as MRD-standard risk (two sensitive targets, MRD negativity at both time points), 8% as MRD-high risk (MRD ³10−3 at time point 2), and the remaining 52% as MRD-intermediate risk. In the previous pilot I-BFM-SG MRD 90 Study conducted on a small group, 10-year EFS were 93%, 74% and 16% in the three groups, respectively [52]. Preliminary analyses of the AIEOP-BFM ALL 2000 confirm the strong prognostic role of MRD; results of the 2000 study are very similar to those of the 90 study for MRD SR and IR groups, but are markedly improved in the HR group (Conter and Schrappe, personal communication). The prognostic role of MRD in day 8 blood or day 29 bone marrow and its relationship to other prognostic variables were assessed by COG. The presence of MRD above 10−3 at day 29 is associated with poor outcome, compared to negative MRD (5-year EFS: 59% vs. 88%). A plethora of studies have documented that gene expression profiling, using DNA microarrays for various types of hematological malignancies, provides novel information, which may have diagnostic and prognostic implications. Searching for genes related to treatment response across different regimens might provide clues about general mechanisms that regulate drug sensitivity in leukemia cells [53]. Whether genes that show independent relationships to treatment response can effectively be incorporated into the existing risk classification is yet to be assessed.

3.  Transplantation in Acute Lymphoblastic Leukemia in First Complete Remission 3.1.  Very High Risk ALL Frontline Treatment Only children carrying very dismal prognostic factors are eligible for HSCT in CR1. They are defined as the VHR or ultra-high risk subset [54, 55]. Patients who fall into the VHR category constitute approximately 8–12% of all children with ALL in most frontline protocols. These patients represent a therapeutic challenge, since remission rates are lower and relapse frequent. Definition of VHR ALL criteria vary across groups and different clinical trials (Table 15-1). Therefore, common efforts are concentrated in finding a consensus on VHR definitions, which is complicated by the fact that the impact of WBC, age, cytogenetics and early response are dependent on frontline chemotherapy protocols [11].

227

Group GATLA

BFM

PINDA

ALL-IC

NOPHO

Country or city

Argentina

Austria, Germany, Switzerland

Chile

Czech Rep., Chile, Uruguay, Hungary, Poland, Israel, Hong-Kong, Croatia, Serbia, Slovakia, Slovenia, Ukraine, Cuba, Moscow

Finland, Norway, Sweden

Next protocol: >5% marrow blasts at day 29, >10−3 MRD at day 79, WBC>200x109/L if no MRD marker, hypodiploid karyotype (<45)

WBC>200, no PR at day 29, 11q23, near-haploidy (modal number <34)

no PR at day 15

t(9;22)

√

√ √

√

√

√

PPR and T-lineage or CD10 negativity or WBC>100 × 109/L or 11q23 rearrangement

√

√

√

no CR at day 33

√

√

√

Infants and age <6 months or WBC >100 × 10 /L or 11q23 Rearrangement or no MRD available

√

√

√

No CR at day 33

√

√

√

PPR and t(9;22) 9

√

√

MRD ³10 at day +33 −2

PPR and T-lineage or CD10- or no PR at day 15 or WBC >100 × 109/L

√

t(9;22) and PPR

√

√

√

no CR at day 78

√

√

√

PPR and t(4;11)

√

√

√

t(9;22)

√

√

√

t(9;22)

√

√

√

MRD ³10−3 at day 78

√

t(4;11)

no PR at day 15 √

√

√

PPR and T-lineage or CD10 negativity or WBC >100 × 109/L or 11q23 rearrangement √

√

√

t(9;22)

MR

IS

Criteria for HSCT in CR1 no CR at day 33

√

√

CB

CB

CB

√

√

√

√

√

√

MUR

√

√

√

√

√

√

MM

Type of Donor Transplantation

Table 15-1.  Eligibility criteria for HSCT in first complete remission in childhood acute lymphoblastic leukemia according to main cooperative groups.

228  A. Balduzzi et al.

√ √ √ √ √ √ √

√ √ √ √ √ √ √

PPR and T or pro-B or WBC >100x10 /L t(4;11) MRD ³1 × 10 at day 78 t(9;22) t(4;11) and PPR no CR at day 33 MRD ³1 × 10 at day 78

COG

USA

√ √

√ √

MLL rearrangement and no CR at day 29 i Amp 21 and no PR at day 7 in HR or 15 in SR or MRD >10−4 at day 29[64]

√ √ √

√ √ √ √

t(9;22) with MRD >10−2 at day 29 Hypodiploid: <44 chromosomes no PR at day 29 −2

no CR or >10 MRD at day 43

√

√

t(9;22)

√

√

√

near haploid and no CR at day 29

√

√

√

no PR at day 29

infant and MLL rearranged and <6 months and WBC >300 or PPR

√

√

t(9;22)

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√*

√*

√*

√

√

√

√

√

√

√

According to center decision

a

IS HLA-identical sibling, MR matched related donor (³ 9/10 matched alleles – 4-digit typing at A,B,C,DRB1,DQB1 loci), MU matched unrelated donor (³ 9/10 matched alleles – 4-digit typing at A,B,C,DRB1,DQB1 loci), MM mismatched donor, includes haploidentical donor and/or partially mismatched unrelated donor (7 or 8/10 matched alleles) and cord blood donor, CB cord blood only, PPR prednisone poor response (³1 × 109/L peripheral blood blasts after 7 day steroid prephase), CR complete remission (M2 marrow: ³5% blasts), PR partial response (M3 marrow: ³25% blasts), MRD minimal residual disease, HR high risk, PB peripheral blood

DCLSG MRC

The Netherlands

United Kingdom

−2

−3

Same as BFM

√

√

MRD ³10−2 at day 35 (semi-quantitative fingerprinting method)

Same as BFM

√

√

Resistance at day 35 (no CR for B-lineage, no PR for T-lineage)

ISPHO

√

√

AUL

Israel

√

√

near haploidy or hypodiploidy

AIEOP

√

√

t(4;11) or any 11q23 rearrangement

Italy

√

√

t(9;22)

9

√

√

PPR and T-lineage or CD10 negativity or WBC>100x109/L

EORTC

France Belgium

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation  229

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A. Balduzzi et al.

3.2.  Eligibility Criteria According to Cooperative Groups At the beginning of the transplant era, prognostic factors in pediatric ALL included male gender, age <1  year or >10  years, high leukemic burden at diagnosis (WBC >50 or 100 WBC × 109/L) and extramedullary involvement (liver, spleen, mediastinum). Subsequently, prognosis has been defined by biological variables: T-immunophenotype, DNA index, chromosome numbers and cytogenetics. Additional features included morphological response after the first 7 days of steroid treatment (peripheral blasts less than 1.0 × 109/L) or marrow response after the first 7 or 14 days of induction treatment (marrow blasts less than 25%). Recently, flow cytometry with or without molecular analysis for MRD after the first 5 and 11 weeks of treatment are regarded to have prognostic significance and are considered for risk assignment. Gene profile microarray analyses are also performed now and may eventually be considered when assigning risk status. VHR childhood ALL, defined by biological characteristics at the onset (high WBC count, T-immunophenotype, t(9;22) and t(4;11) clonal abnormalities) or by resistance to treatment (poor prednisone response, induction failure), yields poor outcome [7, 56–62]. During the last decade, different definitions of HR criteria and different frontline protocols have produced a wide variety of results, with a cure rate ranging from 30% to 60% [56–61]. Eligibility criteria for HSCT as determined by the large cooperative groups are listed in Table 15-1. 3.3.  Results of Transplantation in First Remission Most reports on VHR ALL have compared the two performed treatments (chemotherapy alone or HSCT) in a nonrandomized manner. The data from these studies suggest transplantation from HLA-identical siblings improves the dismal prognosis of childhood VHR ALL, as compared to intensified chemotherapy regimens [64, 65]. In the absence of randomized trials, the results of retrospective reports comparing chemotherapy and transplantation are affected by major biases. First, the selection of patients to be transplanted is influenced not only by the availability of a donor, but also by the risk profile of the patient, as perceived by clinicians during the course of the disease. Second, the waitingtime to transplant causes the transplanted group not to include those patients who do not survive in CR1 long enough to undergo HCT [66]. So comparative studies require careful designs such that patients in both treatment groups are in CR1 and the start time for analysis of outcomes begins at the same time of CR1. It is also important to recognize other factors that may influence the choice of treatment when comparing nonrandomized strategies such as the preference of treating centers, their expertise with HSCT and donor availability [66]. A selection of studies comparing chemotherapy and transplantation outcomes in VHR ALL in CR1 is shown in Table 15-2. Additional data reporting outcome of transplantation in VHR ALL in CR1 are shown in Table 15-3. An international prospective randomized study conducted in seven countries within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG) between 1995 and 2000 showed that VHR ALL children in CR1 benefit from related donor HSCT compared to chemotherapy and survival advantage between the treatment strategies increased as the risk profile of the patient worsened. Criteria for HSCT were homogeneously defined as the characteristics

1995–2000

I-BFM-SG Balduzzi [43]

1993–2002

1995-1998

Japan

29

42

326

55

106

191

357

473

Ph+

Ph+

Ph+

Infants

VHR

VHR T

VHR

VHR

 5

 3

 5

 3

 5

 5

 5

10

25

25

92 (MLL-)* 34 (MLL+)*

42

45

39*

(52)*

(46)

(51)

(41)

(38)*

Legend: VHR very high risk, Ph+ Philadelphia positive chromosome, DFS disease-free survival, ITT intention to treat Legenda: *: EFS; ^: any donor; #: autologous

Milwaukee Talano [44]

1987–2002

1986-1996

1997–2002

Roy [42]

I-BFM-SG Aricò [41]

UKALL

Isoyama [25]

PETHEMA Ribera [67]

Schrauder [39] 1990–2000

Wheeler [65]

UKALL

BFM

1985–1997

References

Group

Time point Recruitment Number of of estimaperiod patients Eligibility tion (years) Chemotherapy HSCT

65

45*

65

45

67

63

45* (72)

(57)

(45)*

68*

45

69

34

Identical sibling Unrelated

DFS (ITT)

Table 15-2.  Comparison of chemotherapy versus transplantation outcomes in childhood ALL in first CR.

51

11/19^ (MLL+ only)*

44 [#]

Alternative

10

3.5

7,3

6,5

6,5

 8

Follow-up (years)

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation  231

Klingebiel, unpublished data

Iori [68]

Eapen and Rocha, unpublished data

Rocha, unpublished data

ALWP-PDWP of EBMT

Roma

CIBMTR and EBMT

Eurocord

1998–2000

1988–2000

Rocha, unpublished data

Klingebiel

Locatelli [69]

Bunin [70]

Dini [71]

Eurocord

ALWP-PDWP of EBMT

AIEOP

NMDP

AIEOP

1989–1998

1995–2004

2000–2007

Eapen and Rocha, unpublished data

2000–2006

2000–2007

2000–2006

1995–2004

1993–1996

CIBMTR and EBMT

CR2

Satwani [54]

References

COG

CR1

Group

167

363

63

48

150

207

108

79

30

22

29

CR2

CR2

pre-, post-1998

CR2

CR2

CR2

CR2

25% younger than 2 years

VHR ( 80% Ph+ and t 4;11)

-

HR

3

5

3

2

2

2

2

2

9

2

20* vs. 67*

VHR

67*

59*

infants vs. no infants

5

32*

38; 36*

27, 58

40; 41*

45 (6 or 7/8 HLA, n = 104)

50 (8/8 HLA, n = 103)

56 (6 or 7/8 HLA, n = 37)

73 (8/8 HLA, n = 42)

46*, ˚

25*

26

34 (haploidentical)

43 (CB)

46 (CB)

30 (haploidentical)

DFS (ITT) after transplantation Time point of estimation (years) Identical sibling Unrelated Alternative

Ph+

VHR

Recruitment Number period of patients Eligibility

Table 15-3.  Outcome of HSCT in ALL.

>3.4

1,5-5,3

5

2

2

1.5

2

5

4

Follow-up (years)

Al-Kasim [79]

Gassas [80]

Eapen [81]

Sanders [82]

Houtenbos [83]

Canada

Canada

NMDP

Seattle

Columbia NY

1984–1994

1982–2003

1998–2006

1990–1998

2001–2005

154

2

6

43

rel

42

37 mm-BM

36 mm-CB-LD 45 mm-CB-HD 38 m-BM

60 m-CB;

41*

76

3

5

3

60*

47*

CR2/3

CR1

BM

282

40

CB

CR2

CR1

2 CR3

13 CR2 3

20

8 CR1

10 CR3

70

63*

55*

33*

46

3

3

3

5

8

4

34 CR2

10 CR1

CR3

CR3

Center experience

CR2

CNS

503

73

82

22

88

35

22

77

56

79

Legenda: *: EFS; §: OS; ~: cord blood; °: adjustment for waiting time to transplant and prognostic factors

Sedlacek [78]

Czech

1987–1999

1990–2002

Afify [76]

Woolfrey [77]

1994–2005

1990–1997

1989–1999

Gassas [75]

Seattle

Any phase

Utah

Canada

CR3

Leiden

Willemze [74]

Bleakley [73]

Australia

CR1 + CR2

Tsurusawa [72]

Japan

60*

63*

49*

78§

35*

32

9*

42*; ~

2

3,8

5,8

10

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which had identified those subsets of children reporting a 4-year EFS of 35% or lower after an intensive chemotherapy regimen based on the BFM backbone [7, 57]. These VHR criteria were (1) failure to achieve CR after the four-drug induction, (2) presence of t(9;22) or t(4;11) clonal abnormalities (conventional cytogenetic or molecular testing), (3) poor response to prednisone (PPR), or (4) WBC equal to or greater than 100 × 109/L. Children were assigned to receive chemotherapy in the absence of a matched related donor or HSCT when a matched related donor was available (biologic randomization). The study accrued 357 patients; 280 were randomized to receive chemotherapy alone and 77 HSCT (Fig. 15-1). The 5-year DFS of those without a matched related donor was 41% compared to 57% of those with such a donor (hazard ratio 0.67, p-value 0.02) [43]. However, 18% of patients deviated from their assigned arm; when analyzed by treatment received, after adjusting for waiting time to transplant, the 5-year DFS for the 259 patients who received chemotherapy was 45%, compared to 63% (p-value 0.08) for the 55 patients who received HSCT from a compatible related donor, and to 34% for the 43 undergoing HSCT from an alternative donor [43]. The novelty of this study was the prospective comparison, which relied on both an a-priori restrictive definition of VHR ALL (8% of the overall population), common to all participating groups, and the randomization by genetic chance, that was performed by assigning the treatment on the sole ground of the availability of a suitable donor, which allowed an unbiased analysis by intention to treat. Standard randomization was not feasible in this framework, as HSCT from a compatible

a

b

Fig.  15-1.  (a) Disease-free survival by donor availability (intention to treat analysis) of 357 children with very high risk acute lymphoblastic leukemia enrolled in the I-BFM-SG prospective study comparing intensive chemotherapy versus allogeneic transplantation from compatible related donor. The 5-year estimates are reported with their corresponding standard error in brackets. (b) Disease-free survival according to treatment performed (adjusted for waiting time to transplant) of 357 children with very high risk acute lymphoblastic leukemia enrolled in the I-BFM-SG prospective study comparing intensive chemotherapy versus allogeneic transplantation from compatible related donor. The 5-year estimates are reported with their corresponding standard error in brackets. CHEMO chemotherapy, HCT hematopoietic cell transplantation, RD related donor, AD alternative donor

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

related donor was widely regarded as more promising, although no evidence of this had ever been previously provided in a clinical trial. Ancillary analyses, focusing on the subsets defined by the VHR characteristics defined in the protocol, showed that patients with induction failure, regardless of other characteristics, benefited the most from an HSCT compared to other subgroups. When VHR was assigned solely on PPR, associated with T-immunophenotype or hyperleukocytosis, outcomes after chemotherapy alone were excellent. While some have observed DFS rates similar to the IBFM-SG [64, 67, 84], others [65] failed to detect an advantage after HSCT. Different definitions for VHR, relatively small numbers of patients limiting their ability to detect statistical significance, different conditioning regimens and delays between achieving CR and HSCT may explain the observed differences. None of these reports address eligibility for unrelated donor transplants as this option was not considered in the study design. Outcome of unrelated HSCT has markedly improved in recent years, mostly due to higher resolution HLA-typing and improved GVHD management [18, 85]. Donor-recipients pairs historically defined “5 out of 6 matched” or “one-locus mismatched” were likely to carry deeper incompatibilities, due to the lower resolution typing routinely adopted in the past. Current typing of A, B, C, DRB1 and DQB1 loci at the allelic level allowed recent experiences to suggest that “9 out of 10” matched transplants yield comparable outcomes to fully matched “10 out of 10” transplants in malignant diseases. As soon as very high risk features and patients’ eligibility are recognized and a compatible related donor is not available, an unrelated donor search should be promptly initiated within worldwide donor registries. Since donor searches require time, transplantation from unrelated donors may occur later than from a related donor [71]. Therefore, apart from eligibility per se, whenever transplantation is delayed either for lack of a suitably matched donor or for the duration of the search process, the risks and benefits of HSCT should be carefully considered. For example, “does HSCT offer an advantage over chemotherapy for a child with ALL who after induction failure subsequently achieved CR and has had sustained remission for 9 months. The impact on prognosis of the time elapsed in CR1, therefore the potential influence of the “waiting time to transplant,” was quantitatively assessed in the same cohort of children previously reported in the I-BFM-SG trial. The conditional 5-year DFS increased from 43% to 44%, 48%, 52% and 60% in patients who maintained their first remission for at least 3, 6, 9 and 12 months, respectively. The overall outcome was constantly better than that obtained with chemotherapy alone and estimates of DFS after HSCT were invariably 10–20% higher than DFS estimates of patients treated with chemotherapy, who had maintained their first remission for at least 9  months. Therefore the relative advantage of transplantation from matched related donors over chemotherapy in VHR ALL was consistent, regardless of the “waiting time,” which is mostly relevant in transplantation from unrelated donors [86–88]. Unpublished data from the CIBMTR and Acute Leukemia Working Party (ALWP) of EBMT have shown that in 79 ALL children transplanted in CR1, from 2000 to 2006, showed 2-year leukemia-free survival rates of 73% after HLA allele matched (HLA-A, -B, -C, -DRB1,) unrelated donor HSCT (n = 42) and 56% for those transplanted with one or more HLA allele mismatched unrelated donors (n = 37).

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3.4.  Outcomes of Umbilical Cord and Haploidentical HSCT Results of allogeneic HSCT with alternative donor/graft such as umbilical cord blood cells or fully haploidentical HSCT for children in CR1 ALL are scarce in the literature, since reports include children with other diseases and all disease phases. In the Eurocord database, 108 children with ALL in CR1 were transplanted with a single unrelated cord blood unit from 2000 to 2007. Majority of those children had VHR ALL [(82% had poor risk cytogenetics, mostly t(9;21) and t(4;11)]. Median age at UCBT was 5 years (0.2–16), (25% were younger than 2 years) and median follow-up was 17 months. TBI was used in 60%, and ATG/ALG in 80%. Majority of the cord blood graft had one or two HLA disparities. Overall 2-year LFS was 46%; 54% for children younger than 2 years and 42% for those who were older. In a recent unpublished survey of the Acute Leukemia and Pediatric Disease Working parties of EBMT results of fully haplo T-cell depleted peripheral blood (PB) HSCT for 102 children with ALL transplanted in CR1 from 1995 to 2004 showed that results of leukemia-free survival (LFS) were improved when the patients received a higher CD34 cell dose and were transplanted in centers with expertise in haplo transplantation. Two-years LFS was 30% for 22 children with VHR leukemia transplanted in CR1. Any comparison of these results should be done with extreme caution due to the heterogeneity of diseases, the small series and advances in the field of alternative donor transplantation. Importantly, the use of umbilical cord blood or a haploidentical donor ensure a donor will be available for virtually all children with VHR ALL in CR1 who meet criteria for allotransplantation. The choice of the donor will depend on factors related to graft acquisition, urgency of transplant, HLA, cell dose and transplant centre expertise (see donor choice).

4.  Acute Lymphoblastic Leukemia in Second Complete Remission 4.1.  Relapsed ALL Relapsed ALL is the fourth most common diagnosis in pediatric oncology and its outcome is dismal. The NCI-risk classification at initial presentation maintains its predictive value, but the main factors affecting outcome after relapsed ALL in children are site of relapse, duration of first remission and immunophenotype [20, 89–94]. Isolated extramedullary relapse (usually involving the CNS or testis), very late relapse, (i.e., occurring beyond 6–12 months after elective discontinuation of chemotherapy) and B-cell precursor immunophenotype ALL have a better prognosis than relapse involving the bone marrow, early relapse and T-immunophenotype ALL [92]. 4.2.  Eligibility Criteria According to Cooperative Groups The BFM stratifies patients into the four groups S1, S2, S3 and S4 as shown in Table 15-4. The S1 group includes patients with late extramedullary relapse, S2 includes an heterogeneous group of patients with early extramedullary relapse, non-T early combined medullary and extramedullary relapse and late medullary relapses, S3 includes B-lineage early medullary relapse and S4 very

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

237

Table 15-4.  Stratification of relapsed acute lymphoblastic leukemia according to the BFM. Non-T

T-lineage

Site of relapse/ Time point after CR1

Extra-BM

BM combined

BM isolated

Extra-BM

BM combined

BM isolated

Very early

S2

S4

S4

S2

S4

S4

Early

S2

S2

S3

S2

S4

S4

Late

S1

S2

S2

S1

S4

S4

BM: bone marrow

early medullary relapse and any T-lineage medullary relapse. A simplified stratification defines S1 patients as low risk, S2 as intermediate risk, and S3 and S4 as high risk. EFS according to the stratification above can be estimated as approximately 70%, 40–50%, 10–20% and 5–10% for S1, S2, S3 and S4, respectively. The BFM ALL Relapse Group (ALL BFM Rez) recently reported 15-year EFS of 30% in 207 with relapsed ALL diagnosed between 1987 and 1990. Five-years EFS of the more recently treated patients within the BFM (1990 and 2000), range between 33% and 49%, with better outcomes associated with strict treatment intensity, that is, shorter time interval between the first and the second induction block [95]. For high risk relapsed ALL the advantage of the immunological effect of an allogeneic graft over chemotherapy has been clearly demonstrated and all cooperative groups consider S3 and S4 patients at such dismal outcome that they are eligible for transplantation from any donor. For patients at low risk of relapse the excellent outcome with chemotherapy alone make them ineligible for HSCT. On the contrary, the treatment of intermediate risk relapsed ALL, that is, S2 patients, is still controversial [96–103]. MRD, a relevant prognostic factor in most frontline protocols, has also been shown to have prognostic significance in relapsed patients and treatment choices were re-directed accordingly [104–107]. In 2001 the retrospective evaluation of MRD in a cohort of 30 relapsed ALL patients, treated within the various ALL Rez BFM protocols, allowed the BFM Group to show the strong prognostic impact of early high-level MRD. Patients whose MRD was <10−3 at day 36 reported a 6-year EFS of 86%, while patients whose MRD was >10−3 at day 36 reported a 6-year EFS of 0%. Thereafter, the BFM group agreed to adopt a MRD-based stratification to direct treatment choices in S2 patients. Patients whose MRD rapidly improves are judged to have a very good outcome (above 65%) with chemotherapy associated with cranial radiotherapy, while when MRD does not promptly decrease after induction chemotherapy allogeneic HSCT (expected outcome <20%) is recommended instead of chemotherapy. In most ongoing relapse protocol, after the BFM, many cooperative groups adopted a MRD-based stratification, so that S2 patients are eligible for transplantation from a compatible donor according to their MRD level after the first month of treatment. The cut-off varies among groups between 10−3, adopted by BFM and COOPRALL, 10−2, adopted by the MRC, and 10−4, which is under investigation for the next European cooperative relapse protocol. Despite still in its planning phase, investigators are considering to enlarge

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eligibility to transplantation by adopting a lower cut-off of MRD (>10−4) after the second induction course to identify patients who may benefit of allogeneic transplantation. Current eligibility criteria for transplantation are reported in Table 15-5 for most cooperative groups. In summary, in the ongoing BFM relapse protocol S2 patients are eligible for transplantation from HLA-identical sibling donors, but transplantation from an unrelated donor is recommended only for those with a high MRD level (>10−3) after the second induction course. The Netherlands and Czech Republic adopt the same criteria as BFM. In the COOPRALL protocol transplantation from HLA-identical sibling is recommended for S2 patients with MRD >10−3 after induction and transplantation from unrelated donor is allowed in most early CNS relapse. In the ongoing AIEOP protocol S2 patients (medullary relapses beyond 48 months after diagnosis are excluded) are eligible for transplantation from either related or unrelated HLA-matched donors, but not from a partially mismatched related donor, unless a high level of MRD is detected after 3 months of treatment. In the United Kingdom early and very early CNS relapsed children are eligible for transplantation from any donor, while S2 patients overall are eligible for transplantation from either related or unrelated HLA-matched donors if the MRD level is >10−2 at day 35. In the United States, S2 patients are eligible for transplantation from HLA-identical sibling donors. Such lack of homogeneity discloses the lack of evidence of the optimal treatment, which would justify a randomized trial. Nevertheless randomization between chemotherapy and transplantation is hardly feasible and likely to fail, as previously demonstrated by other groups in the same or different settings. It is always difficult to counterbalance the advantage of higher efficacy with the drawbacks of early mortality and long-term toxicity. Generally, optimizing strategies aim at ensuring the best available treatment by sparing toxicity without jeopardizing ultimate outcome. It is difficult to find a consensus, particularly regarding treatment of S2 children, but possibly the next cooperative European relapse protocol will match the aim of re-defining the role of transplantation in S2 patients. HSCT sequelae may not be counterbalanced by a potential little improvement in MRD-low patients and its efficacy could even be not sufficient in MRD-high patients. Infertility and increased incidence of endocrinological problems, growth impairment, early cataracts, organ impairment, and second malignancies are to be expected after transplantation compared to chemotherapy, often associated with immunological complications, that is, graft-versus-host disease and infections, due to highly impaired immune-reconstitution. Lower complication rates are expected for not transplanted children, even if their treatment invariably includes cranial irradiation, which also increases the risk of brain tumors [9, 108–111]. 4.3.  Results of Transplantation in Second Remission Two major biases affect retrospective studies in relapsed ALL. First, the selection of patients for transplantation is not only dictated by the availability of a donor, but also influenced by the risk profile of the patient, as perceived by clinicians during the course of the disease. Second, patients not achieving second CR (CR2) or dying while waiting for HSCT are not taken into consideration in the HSCT studies [66].

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

239

Table 15-5.  Eligibility criteria for transplantation in second complete remission in childhood acute lymphoblastic leukemia according to main cooperative groups. Type of transplantation Country

Group

Criteria

Argentina

GATLA

Same as BFM

Austria, Germany, BFM Switzerland

IS

MR

MUR

MM

S1 S2 late medullary (isol or comb) with PB blasts <106/L and with MRD <10−3 at day 33 S2 extramedullary CNS or testis unilateral S2 late medullary (isol or comb) with PB blasts <106/L and no MRD at day 33 available

Ö

S2 late medullary (isol or comb) with PB blasts <106/L and with MRD <10−3 at day 33

Ö

Ö

Ö

S2 late medullary (isol or comb) with PB blasts <106/L and with MRD ≥10−3 at day 33

Ö

Ö

Ö

S2 late medullary (isol or comb) with PB blasts >10 × 109/L and no MRD at day 33 available

Ö

Ö

Ö

S2 extramedullary bilateral testis

Ö Ö

Ö Ö

Ö Ö

Ö Ö

S3/S4

Ö

Ö

Ö

Ö

S2 if MRD not available

Ö

Ö

ÖCB

Ö

S3/S4

Ö

Ö

ÖCB

Ö

S2 early combined and with MRD <10−3 at day 33

Chile

PINDA

Czech Rep.

CPH

Same as BFM

Israel

Israel SPHO

Same as BFM

Finland Norway Sweden

NOPHO

*

France

COOPRALL

Non-T CNS female

Belgium

S2 with MRD <10−3

Portugal

S1

Italy

AIEOP

S2 with MRD >10−3

Ö

T early or very early CNS

Ö*

Ö*

Ö*

Non-T very early CNS male, early CNS male >6 years

Ö*

Ö*

Ö*

All S3/S4, t(9;22)

Ö

Ö

Ö

S2 with CR1 duration >48 ms S2

The Netherlands

DCLSG

Ö

Ö

S2 with CR1 duration <48 ms

Ö

Ö

Ö

S2 with MRD >5 × 10−4 at 3 ms

Ö

Ö

Ö

Ö

S3/S4

Ö

Ö

Ö

Ö

Same as BFM (continued)

240 

A. Balduzzi et al.

Table 15-5.  (continued) Type of transplantation Country

Group

Poland

Criteria

IS

MR

B-lineage late medullary with persistent MRD

Ö

Ö

MUR

MM

combined without high MRD level

Ö

Ö

B-lineage early combined

Ö

Ö

Ö

Late medullary with persistent MRD (isolated or combined)

Ö

Ö

Ö

Late combined

Ö

Ö

Ö

T-ALL

Ö

Ö

Ö

Ö

B-lineage very early/early medullary (isolated or combined)

Ö

Ö

Ö

Ö

S2 and MRD >10−2 day 35 RS

Ö

Ö

Ö

S3/S4

Ö

Ö

Ö

Ö

t(9;22) with persistent MRD

United Kingdom

MRC

Ö

Early/very early CNS relapse USA

COG

B-lineage late medullary

Ö

Early isolated extramedullary Any T-lineage medullary

Ö

Ö

Ö

B-lineage early medullary

Ö

Ö

Ö

IS HLA-identical sibling, MR matched related donor (³ 9/10 matched alleles – 4-digit typing at A,B,C,DRB1,DQB1 loci), MU matched unrelated donor (³ 9/10 matched alleles – 4-digit typing at A,B,C,DRB1,DQB1 loci), MM mismatched donor, includes haploidentical donor and/or partially mismatched unrelated donor (7 or 8/10 matched alleles) and cord blood donor, CB cord blood only, PPR prednisone poor response (³1 × 109/L peripheral blood blasts after 7 day steroid prephase), CR complete remission (M2 marrow: ³5% blasts), PR partial response (M3 marrow: ³25% blasts), MRD minimal residual disease, HR high risk, PB peripheral blood * According to center decision

Some investigators retrospectively reported results after chemotherapy and transplantation in ALL in CR2, as listed in Table 15-6, attempting to overcome major biases by adjusting for the waiting time to transplant. Particularly in late relapses, the advantage of HSCT from matched related donors becomes more apparent with each successive year of follow-up, suggesting greater protection against late relapses than with chemotherapy alone in patients who survived the early toxic effects of treatment, so that a long follow-up is needed to account for chemotherapy failure, in a way “diluted overtime.” A selection of studies comparing outcome of chemotherapy and transplantation in ALL in CR2 is shown in Table 15-6. Borgmann and Eapen reported chemotherapy results after matching for most relevant known prognostic variables with the transplanted patients [88, 100].

1995–1998 214

Gaynon 98

COG

30* 26*

Overall

Overall  5 CR2 (76) Isol. BM

Matsuzaki112 1984–1996 117 Ped Blood Cancer, 2005

Rivera142 Cancer, 2005

Japan

St. Jude

 6

 5

22*

17*

(20)

(45)*

(44)*

38^

42*

59*

58

42

45*

30 without TBI (44)*, ˚

52* (31) *, ˚ 47 *; #

(29)

(46)*

(54)*

60 *

30 *

38 #

29 (21)

43*, #

(47)*, ˚

10

>10

9

8

6

5

8

9

60 with TBI

8

8 without TBI

2

Follow-up Alternative (years)

41 with TBI

46§

Unrelated

DFS (ITT) Transplantation Identical sibl.

Legenda: *: EFS; §: OS; ^: any donor; #: autologous; °: adjustment for waiting time to transplant and prognostic factors

1984–1994 106

Matched pair CR2

Borgmann100 1983–2001 162 Blood, 2003

30*

BFM

15

Overall

Einsiedel95 1987–1990 183 JCO, 2005

66

BFM

Matched  8 pair, CNS

Eapen96 Leuk, 2008

1990–2000 209

 5

 5

COG-CIBMTR

JCO, 2006

Overall

1982–1997 231

Harrison101 AnnOn, 2000

MRC CLWP

Early BM

UKALLR1

1991–1995 243 Lawson94 BJH, 2000

UKALL

48*

59

Late  5

23

Matched  8 pair, early

1991–1997 374

39§

Eapen97 Blood, 2006

10

COG-CIBMTR

Eligibility Overall

N

Saarinen141 1981–2001 854 JCO,2006

Period

Time point of estimate (years) Chemotherapy

NOPHO

Group

author journal/ publ year

Table 15-6.  Comparison of chemotherapy versus transplantation outcomes in childhood ALL in second CR.

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242 

A. Balduzzi et al.

Borgmann et  al., in a matched-pair analysis, compared children in CR2 receiving either chemotherapy or unrelated donor HSCT matching for site of relapse and immunophenotype, and, as closely as possible, duration of first remission, age, diagnosis date and peripheral blast cell count at relapse. The study could not show a significant difference in EFS between unrelated-HSCT and chemotherapy in 28 patient pairs with intermediate prognosis (39% vs. 49%, respectively) whereas EFS was significantly different in the 53 pairs with poor prognosis (44% vs. 0%, respectively), showing that unrelated-HSCT provides better EFS for patients with high risk relapsed ALL [100]. The Center of International Blood and Marrow Transplant registry (CIBMTR) and the COG compared outcomes in 188 patients in CR2 enrolled in chemotherapy trials and 186 HLA-matched sibling transplants, treated between 1991 and 1997. The relative efficacy of chemotherapy and transplantation depended on time from diagnosis to first relapse and the transplant conditioning regimen used. For children with early first relapse (<36 months), risk of a second relapse was significantly lower after total body irradiation (TBI)-containing transplant regimens than chemotherapy regimens. In contrast, for children with a late first relapse (>36  months), risks of second relapse were similar after TBI-containing regimens and chemotherapy, confirming the advantage of HLA-matched sibling donor transplantation using a TBI-containing regimen in CR2 for children with ALL after an early relapse [97]. The inclusion of pre-emptive CNS directed therapy as part of frontline treatment for ALL has led to significant decreases in meningeal relapse. Nevertheless, approximately 2–10% of children experience isolated CNS relapse. Outcome after chemotherapy is generally poor, particularly in older males with T-immunophenotype, and variable results are reported after HSCT. Though randomized trials are lacking, there is general agreement that when relapse occurs early (<18 months after diagnosis) the outcome of either treatment is dismal. Thus outcomes of 149 patients enrolled on two recent POG chemotherapy trials between 1990 and 2000 and 60 HLA-matched sibling transplant recipients reported to the CIBMTR during the same period were compared. The overall 5-year EFS was 46% and CR1 duration, site of relapse, age at diagnosis and gender emerged as factors of prognostic significance. The 8-year DFS adjusted for age and duration of CR1 were similar after chemotherapy with irradiation and transplantation (66% and 58%, respectively), suggesting that transplantation did not offer an advantage over an intensified chemotherapy approach with irradiation. A lack of graft-versus-leukemia effect in the CNS, higher transplant-related mortality after HSCT and the excellent EFS with an intensified chemotherapy and irradiation regimen explained why outcomes were similar in the two treatment groups [96]. The MRC reported the experience in the United Kingdom in relapsed ALL of the UKALLR1 study, running in 1991–1995. The overall 5-year EFS was 46% and CR1, site of relapse, age at diagnosis and gender emerged as prognostic factors. Five-year EFS was only 7% for very early medullary relapses, 35% for early medullary, 39% for very early extramedullary, 44% for early extramedullary, 57% for late medullary, and 77% for late extramedullary relapses (S1). For those receiving chemotherapy alone, the 5-year EFS was 48%, for autologous bone marrow transplantation 47%, for unrelated and related donor transplantation 52% and 45%. The groups, however, were not comparable with respect to risk factor profile, since patients were more likely

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

to be transplanted if they were at higher risk; therefore direct comparison of EFS is misleading. When adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, no particular treatment resulted of benefit. The planned randomization between autologous transplantation and conventional chemotherapy for patients without a matched allogeneic sibling donor failed with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials in this setting [91]. The subsequent UKALL R2 MRC study, enrolling 150 relapsed children between 1995 and 2002, reported an overall 5-year EFS of 47%. The duration of first complete remission and immunophenotype, but not sites of relapse, was predictive for survival. According to the BFM relapse stratification, 5-year EFS for standard, intermediate and high risk groups were 92%, 51% and 15%, respectively. In the IR group, those with a very early isolated central nervous system relapse had a dismal outcome [94]. In the Australian analysis by intention to treat, the availability of a matched family donor improved 8-year EFS from 9% to 55% [73]. An AIEOP study retrospectively conducted “by intention to treat” between 1988 and 1998 reported the outcome of 167 consecutive children in CR2 ALL for whom an unrelated donor search was initiated at a median time of 2 months after relapse. A suitable donor was identified for 70 patients at 1 year after search activation before 1995 and 6.5 months after 1995. Further leukemia relapse occurred during the search in 94 children at a median of 4 months after search activation, 36 of whom underwent transplant from unrelated (14) or alternative (22) donors beyond CR2, while 58 died of disease progression. Of 78 patients not experiencing a second relapse, 64 underwent unrelated (46) or alternative (18) donor transplant, while of the 9 proceeding with chemotherapy, only 4 survived. The 3-year DFS for the 167 patients was 15%, and survival 25%, whereas after transplant for the 60 unrelated and 40 alternative donor transplanted children it was 31% and 25%, respectively. In conclusion, a 31% 3-year EFS was reported after unrelated transplant in CR2 ALL, but only 38% of the eligible patients could access the procedure, since relapse during the search jeopardized its feasibility [71]. In 163 patients with very early medullary relapse a 5-year DFS of 20% with chemotherapy and 42% with transplantation from HLA-identical sibling was reported by the COG [98]. In 93 patients experiencing very late relapse at >60 months after diagnosis the AIEOP reported a 40% 5-year DFS [93]. In multivariate analysis, the site of relapse was the only significant predictor of outcome, with patients with isolated bone marrow relapse with 5-year EFS of 25% compared with those with combined or isolated extramedullary relapse (5-year EFS 51% and 68%, respectively). All seven patients undergoing an allogeneic bone marrow transplantation from a matched related donor are alive in CR2 [93]. A Japanese study reported a 25% EFS in 90 relapsed patients achieving CR2. The significant prognostic factors identified by a multivariate analysis included the time of relapse (EFS: early 16%, intermediate 24%, late 35%) and the treatment after relapse (EFS after transplantation 30%, chemotherapy 22%) [112]. The NMDP retrospective study reviewed the outcomes of 363 children in CR2 ALL receiving unrelated donor transplant from 1988 to 2000. DFS at

243

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A. Balduzzi et al.

5 years was 36% overall and was significantly worse for patients 15 years or older. Acute GVHD developed in 71% of the patients, with 29% having grades III-IV and the incidence of chronic GVH disease was 39%; TRM was 42% and was associated with HLA mismatches, age 15 years and older, and early relapse [70]. The AIEOP described a significant improvement of outcome after unrelated donor transplant in ALL in CR2 from a 3-year EFS of 27% before 1998 to 58% after 1998, suggesting that outcome after transplantation from unrelated donors is becoming more and more similar to the outcome after HLA-identical siblings, as expected with higher resolution HLA typing and better donor recipient matching [69]. Recently, an unpublished collaborative survey on behalf of CIBMTR and EBMT has shown that in 207 ALL children transplanted in CR2, from 2000 to 2006, 2 years-LFS of HLA allele matched (HLA-A, -B, C-, DRB1, or 8/8) unrelated HSCT (n = 103) was 50% and it was 45% for those transplanted with one or two HLA allele mismatched unrelated HSCT (n = 104). (Table 15-3) 4.4.  Outcomes of Umbilical Cord and Haploidentical HSCT In the Eurocord database, 150 children with ALL in CR2 were transplanted with a single unrelated cord blood unit from 2000 to 2007. Two-year LFS was 43%. In a risk factor analysis the most important factor associated with LFS was the time from CR1 to CR2. The 2-year LFS was 45% for those patients relapsing 24 months after CR1 or later compared to 26% for those with an earlier relapse (unpublished data). In a recent survey of the Acute Leukemia and Pediatric Disease Working Parties of EBMT, 48 children with ALL were transplanted in CR2 with a fully haploidentical T-cell depleted PB. At 3 years, LFS, relapse and nonrelapse mortality were 34%, 36% and 60%, respectively. As already stated for patients in CR1, any attempt to compare outcomes between haploidentical and cord blood HSCT for patients in CR2 should be cautious given the heterogeneity of disease, the small series of patients, and developments in the field of alternative donor transplantation. The choice of the donor depends on factors not only related to the patients, but also to the expertise of each transplant centers (Table 15-7). 4.5.  Acute Lymphoblastic Leukemia in Advanced Phase All working groups agree on the eligibility for transplantation of all CR3 ALL from any donor, even though their risk of subsequent relapse is very high. Furthermore, transplantation in CR3 is associated with a high risk of transplant-related mortality, due to the pre-existing high cumulative organ toxicity [75–77]. Given the poor outcome of a second relapse, new strategies are required to identify those patients who will most benefit from stem cell transplantation already in CR2, particularly in the intermediate, most heterogeneous risk group. Findings in transplantation in CR3 ALL are reported in Table 15-3. The prognosis of relapse after transplant is severe, with the possibility to rescue fewer than 5–10%, as reported in limited series, mixed with adults and other diseases [113]. New experimental approaches and cell therapy may be applied for in these subset of patients [114].

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

Table 15-7.  Advantages and limitations of unrelated donor BMT, UCBT and haploidentical HSCT from a relative, and criteria to be considered for choosing an alternative donor for patients without an HLA-identical sibling. UBMT

UCBT

Haplo-HSCT

A, B, DRB1 molecular typing availability

16–56%

~80%

100%

Median search duration

3–6 months

<1 month

Nil

Unavailability of identified donors

20–30%

~1%

None

Rare haplotypes representation

2–10%

20%

None

Main limiting factor to graft acquisition

HLA compa­ tibility

Cell dose

Poor mobilization

Transplant date planning

Difficult

Easy

Easy

Potential for immunotherapy

Yes

No

Yes

Potential for viral transmission to recipient

Yes

No

Yes

Potential for unknown conge­ nital disease transmission to recipient

No

Yes

No

Risk for the donor

Very low

No

Very low

Main open clinical issues

GvHD

Graft failure, delayed immune recovery

Delayed immune recovery, lack of T-cell mediated GVL effect

*Modified from reference [17].

5.  Factors Related to HSCT Procedure 5.1.  Stem Cell Source: Bone Marrow, Peripheral Blood and Cord Blood The recommended source of stem cells is bone marrow and no randomized trials have been conducted in pediatric Acute Lymphoblastic Leukemia between bone marrow (BM) and G-CSF mobilized peripheral blood stem cells transplants (PBSCT) from HLA-identical sibling donors. However, in a retrospective-based registry analysis, Eapen, on behalf of CIBMTR, compared 143 children with acute leukemia receiving PBSCT with 630 BMT. Hematopoietic recovery was faster after PBSCT, risks of grade 2 to 4 acute GVHD were similar, but chronic GVHD risk was higher after PBSCT. In contrast to reports in adults, treatment-related mortality, treatment failure and mortality were higher after PBSCT. Risks of relapse were similar. These data suggest poorer outcomes after PBSC compared with BM transplantation, therefore in the absence of prospective trials, use of PBSC in this setting should be avoided [115]. In the unrelated transplant setting, only a recent unpublished collaborative study has addressed the question. The CIBMTR, in collaboration with the EBMT, has compared 385 unrelated BMT with 110 unrelated PBSCT in children with acute leukemia. Children transplanted with PBSC had higher risk of chronic GVHD but not different outcomes such as acute GVHD, NRM, relapse or LFS compared to BMT. In this study the follow-up was still short to detect an effect of PBSC and chronic GVHD on late outcomes. In order to

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circumvent the problem of the chronic GVHD with PBSC, one could suggest a graft T-cell depletion. However, there is a consensus that the graft should not undergo T-cell depletion, unless in case of mismatched/haploidentical donor [116, 117]. In the last decade, HLA-mismatched umbilical cord blood cells have been used as an alternative source of stem cells for allogeneic HSCT in the unrelated transplant setting for children and young adolescents (CIBMTR unpublished data). Outcomes of unrelated cord blood transplants (UCBT) have been compared to HLA antigen and allele matched bone marrow in many retrospective studies. In summary, neutrophils recovery is delayed, acute GVHD decreased and LFS not different from HLA-matched unrelated BMT if the cord blood graft contains higher numbers of nucleated cells and not more than two HLA disparities [17, 81]. Specific analyses of outcomes after UCBT in children with ALL are missing in the literature. Recently, the Eurocord group has analyzed 323 children with ALL receiving a single unit UCBT. Seventysix children were transplanted in CR1, 136 in CR2 and 111 in more advanced phases of the disease. Among these children poor cytogenetics were observed in 89% of children in CR1, 33% in CR2 and 42% in advanced phases. Twenty percent of children transplanted in advanced phases had been previously autografted. The median age was 6.5 years at UCBT, median cell dose infused was 4.1 × 107/kg and the median follow-up time was 22 months (3–96). The cord blood was HLA 5/6 in 46%, 4/6 in 39%. All children received myeloablative conditioning regimen (TBI in 66%). Cumulative incidence of neutrophil recovery at day 60, acute (grade II-IV) and chronic GVHD were 76%, 42%, 14%, respectively. Overall 2-year LFS was 42% for patients transplanted in CR1, 41% for those in CR2 and 24% for those transplanted in an advanced phase. In a multivariate analysis, only CR1 or CR2 were associated with better LFS (HR = 1.8; p < 0.0001). In a risk factor analysis for patients transplanted in CR2 only shorter time from diagnosis to first relapse unfavorably affected LFS, which was 45% for children relapsing after 2 years of treatment compared to 26% of those presenting with earlier relapse [118]. 5.2.  Donor Choice: Unrelated, Cord Blood or Haplo Hematopoietic Stem Cells? The use of alternative HSC donors has witnessed significant progress, mainly due to (1) better HLA matching at the allelic level between the unrelated donor and recipient translating into better patient outcome; (2) better donor choice and patient selection in unrelated, often HLA-mismatched, cord blood transplantation; and (3) new strategies of adoptive cell therapy, aimed at improving results of T-cell depleted haploidentical HSCT from a relative. Currently, it is possible to find a donor for virtually almost all children with an indication for allogeneic HSCT as long as stem cell source and degree of matching are considered appropriate for the risk profile of the patient. When an HLAidentical sibling is not available, as it occurs in 3 out of 4 children in need of a HSCT [43], one of the three options of HSCT from alternative donor/graft is available. Importantly, each of these options has advantages and limitations. Therefore, any physician considering alternative donor has to carefully evaluate all options, for each pediatric patient in need of an allograft, in order to choose the best donor, taking into account the urgency of transplantation,

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

donor characteristics and center experience. Advantages and limitations of each of the three options and main criteria to choose an alternative donor for pediatric patients lacking an HLA-identical sibling is not available are presented in Table 15-7 [17]. 5.3.  UCBT Compared to BMT from Unrelated Donors Three published reports, namely two single centre studies and a Eurocord registry analysis, have compared the outcome of UCBT and UBMT in children, most of them with acute leukemia [119–121]. Briefly, in these three studies, recipients of UCBT were transplanted earlier, had delayed neutrophil and platelet recovery and reduced incidence of acute GvHD as compared to children given a UBMT. Nevertheless, the overall survival (OS) probability was not significantly different in UCBT or UBMT pediatric recipients [119–121]. Recently, a meta-analysis combining these comparative studies was published [122]. A total of 161 children undergoing UCBT (mostly one or two antigenmismatched) and 316 children undergoing UBMT (HLA defined as low resolution typing of HLA-A and -B and high-resolution typing of HLA-DRB1) were analyzed; this study could detect no differences in 2-year OS between children given an unrelated UCBT or UBMT. In a more recent analysis, Eapen et al. [81] have compared results observed in 503 UCBT recipients with those of 282 UBMT recipients [116 were HLA allele-matched (HLA-A, -B, -C and DRB1, thus 8 out of 8) and 166 mismatched]. Of the UCBT recipients, 35 were matched at the HLA A, B (antigen-level) and DRB1 (allele-level), 201 were mismatched at 1-locus and 267 were mismatched at 2-loci. All patients (aged <16 years) had acute leukemia. In comparison with children given an allele-matched UBMT, patients transplanted with 1 or 2 HLA-disparate UCB unit had a similar 5-year DFS (45% for patients given a 1-antigen disparate UCBT with a cell dose greater than 3 × 107/kg nucleated cells, decreasing to 36% with a lower cell dose, and 33% for patients given a 2-antigen disparate UCB vs. 38% in allelic-matched UBMT), while an even possible better outcome was evident for the 35 children given HLA-matched UCBT, the 5-year DFS being 60%. TRM rates were higher after transplants of 2-antigen HLAmismatched UCB (relative risk 2.31, p = 0.0003) and possibly after 1-antigen HLA-mismatched UCB units containing less than 3 × 107/kg nucleated cells (1.88, p = 0.0455). By contrast, the incidence of relapse was lower after 2-antigen HLA-mismatched UCBT (0.54, p = 0.0045). These data support the use of HLA-matched and 1- or 2-loci HLA-mismatched UCB in children with acute leukemia when a good cell dose is available [123]. 5.4.  Comparison of Unrelated Cord Blood with Haploidentical Transplantation in Children with Acute Lymphoblastic Leukemia The Eurocord group, in collaboration with the ALWP and the PDWP of the EBMT, has compared the outcome of patients given either UCBT or Haplo-HSCT, by performing a retrospective comparison of pediatric patients (16 years or younger) with high risk ALL [124]. Children had received either Haplo-HSCT (n = 118) or UCBT (n = 341) in EBMT-Eurocord centers between 1998 and 2004. Haplo recipients tended to be older and to have CMV positive serology and t(9;22) more frequently. The median follow-up was 56 months and 24 months for Haplo-HSCT and UCBT patients, respectively. Failure of

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engraftment was significantly higher following UCBT than after Haplo-HSCT (23% vs. 11%, p = 0.007). In multivariate analysis, adjusted for differences between groups and prognostic factors, relapse incidence was higher in HaploHSCT recipients compared to UCBT (relative risk = 1.7, p = 0.01), but TRM and DFS were not significantly different. In conclusion, in pediatric patients with ALL, UCBT is associated with inferior rate of engraftment, higher incidence of grade II-IV acute GvHD and lower incidence of relapse compared to Haplo-HSCT; however, there was no difference in terms of TRM and DFS. Therefore, in the absence of an HLA-identical donor, both strategies are suitable options to treat a child with high risk ALL. 5.5.  Transplantation Procedure: Conditioning Regimen Fully myeloablative conditioning regimens are recommended, while reduced toxicity or reduced intensity conditionings are to be limited to patients undergoing second transplant or with contraindication to full-intensity conditionings due to comorbidities. The conditioning regimen has a significant impact on survival and incidence of relapse. While studies in acute myeloid leukaemia generally indicated comparable antileukemic efficacy of TBI and busulfan, specific ALL data showed a significant benefit of TBI-containing conditioning regimens, therefore TBI is highly recommended in ALL [125–127]. In 1991 in a retrospective study Dopfer showed the superiority of TBI associated with etoposide as a single drug to other conditioning regimens [99]. In the I-BFM transplantation prospective study, the transplantation is planned to be performed within a recommended time frame of at least 2  months after achievement of remission and within 5 months after diagnosis. GVHD prophylaxis consists of cyclosporine 3 mg/kg/day and the conditioning regimen consists of hyper-fractionated total body irradiation (2 Gy bid on days −6, −5, −4) and etoposide (60 mg/kg i.v. on day −3) for patients older than 2 years, and busulphan (5 mg/kg/day p.o. on days −8, −7, −6, −5), cyclophosphamide (60 mg/kg/day i.v. on days −3, −2) and melphalan (140 mg/mq i.v. on day −1) for patients younger than 2 years. The Nordic Bone Marrow Transplantation Group reported a randomized study comparing cyclophosphamide plus either busulfan or TBI and were able to show an advantage of TBI in terms of early toxicity and mortality reduction and a trend for a lower relapse-free survival (50% vs. 36%) [128]. Davies retrospectively compared two cohorts of ALL children transplanted from HLA-identical siblings reported to the IBMTR who received a TBI- or non-TBI-containing conditioning regimen. This latter may be associated with fewer late effects and is logistically easier to administer. The 451 children conditioned with cyclophosphamide and TBI versus the 176 conditioned with BU/CY at 3 years reported higher survival (55% vs. 40%,) and leukemia-free survival (50% vs. 35%), and lower TRM (15% vs. 23%) and a trend for a lower cumulative incidence of relapse (35% vs. 41%) [14]. Other conditionings containing TBI, either associated with cyclophosphamide as a single drug or in association with other drugs, are commonly adopted. The AIEOP reported good results with the conditioning consisting of TBI, thio-tepa and cyclophosphamide, yielding a 3-year DFS of 65% in 40 CR1 and CR2 ALL patients, with only one non-leukemic death and eight relapses [129].

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

One could expect that a previous TBI could jeopardize the feasibility of a second transplant; on the contrary many recent reports show that a reduced toxicity conditioning, often consisting of fludarabine and treosulfan, is feasible with very low toxicity [130]. 5.6.  Toxicity and Mortality The long-term effects of TBI are well documented, with growth impairment, cataracts, gonadal failure and hypothyroidism occurring in substantial numbers of patients and sterility almost invariably. The risks of secondary malignancy are also increased by TBI. Transplantation issues in pediatrics present unique challenges, since influences on growth and development are important factors in the evaluation of treatment outcomes [14]. All organs and tissues can be injured by the pretransplant conditioning, but only the hematopoietic bone marrow is replaced. Except for GVHD, autografting can result in similar sequelae from the transplant-conditioning regimen used. These complications occur in survivors cured of their leukemia, but can carry with them a significant burden of morbidity (legacy of growth, endocrine and neuropsychological disturbances, organ failure and high risk for second cancers) and in some cases, mortality unrelated to their leukemia [82, 131– 133]. Curing the child demand that the risk of adverse sequelae of treatment administered is carefully balanced with known therapeutic benefits [134]. 5.7.  MRD and Allogeneic Transplantation Chimerism analysis has become an important tool for transplant surveillance to monitor engraftment, graft rejection and can be used as an indicator for the recurrence of the underlying malignant disease [135–138]. Molecular analysis was adopted to assess the kinetics of detecting negative MRD after diagnosis, relapse, and after transplantation as well. The maintenance of molecular remission after transplantation in subsequent marrow aspirates sampled before HSCT and every 3 months up to 1 year after transplantation allowed some investigators to assess the prognostic role of MRD before and after transplant. Patients who are MRD positive at time of transplantation have an increased risk of relapse after transplant, suggesting that residual leukemia could not be eradicated either by the conditioning regimen or the immunological alloreactivity [107]. The adoption of additional treatment elements, as “FLA-DNXM,” or “AMSA-FLA” in patients who do not clear their MRD before transplant, aims to reduce leukemic burden and optimize the antileukemic effect of transplantation. Nevertheless MRD analyses at transplant and thereafter, adopted in recent years, represent crucial tools which may contribute to further improve results in VHR CR1 or CR2 patients. Since 1998, reports from three European centers have shown that MRD burden prior to conditioning is the strongest single predictive factor for relapse after HSCT [104, 106]. Recognition of the potential clinical impact of this test has led to the formation of a European Study Group on MRD detection in transplantation for ALL. Although formal meta-analysis is invalidated by differences in transplant protocol and MRD assay method, some clinically useful conclusions can be

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inferred by pooling results. First, it is clear that EFS for the MRD-negative group is uniformly good; second, in the MRC and Dutch studies, transplantation in children with high-level disease appears futile, whereas the BFM results suggest a minority of such children can be cured. It is intriguing to speculate whether differences in transplant protocol may explain the observed differences in outcome. A third observation common to these studies is the trend towards a high MRD level in children who relapse in the bone marrow after a short CR1, indicating that relative insensitivity to therapy underlies the high risk of relapse after transplant in such patients. It is important to acknowledge that current evidence regarding the clinical significance of MRD is based on retrospective studies of selected groups of patients. The small numbers of children treated at any one center argue strongly for both national and international cooperation. A major drawback of such studies in the past has been failure to agree to a common transplant protocol. Future common protocols should address two issues: (1) novel therapies for those with high-level MRD pretransplant and (2) definition of a low-risk group who can be cured without transplant. Many ongoing protocols manage high-level MRD patients by potentiating the graft-versus-leukemia effect. Thus, immunosuppression is tapered and discontinued early in children with MRD positivity before transplant and consecutive increasing doses of donor lymphocyte infusion may be added. The next European relapse protocol will contain a window therapy arm for those found to be high-level MRD positive prior to conditioning. Currently, a combination of fludarabine, high-dose cytosine and liposomal daunorubicin is being used in this window. If this approach failed, new drugs or monoclonal antibodies may be examined.

6.  Conclusions International collaboration among the large cooperative pediatric ALL working groups has allowed us to advance leukemia research [139]. The role of transplantation will evolve depending on chemotherapeutic regimens used. For any given patient the decision to allograft reflects a balance between the biology of the disease and the risk of transplant-related death and long-term sequelae. At present, information about the biology of the disease is based on known prognostic factors, including WBC, cytogenetics, and morphological and molecular assessment of response to therapy at various time-points. The risk of mortality is a function of HLA disparity between donor and recipient, performance and remission status [105]. Although the indications for transplantation in CR1 vary among the major treatment co-operatives, the procedure is strictly reserved for those with very high risk biologic features and a poor early response, however defined. There is a consensus that prognosis after relapse is dependent on the duration of first remission and the site of relapse. MRD-based stratification may further optimize the identification of patients who need the alloreactive effect of an allograft to be cured [105]. Pediatricians particularly recognize the need not only to increase the cure rate, beyond the 80% achieved with contemporary treatments, but also to improve the quality of life of leukemia survivors by limiting both acute and long-term sequelae [106].

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation 

Acknowledgments  We would like to thank the following colleagues who were asked and who provided eligibility criteria for transplantation on behalf of each cooperative group, as reported in Tables  15.1 and 15.5: Eduardo Dibar for GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda); Martin Schrappe, André Schrauder, Arend von Stackelberg and Christina Peters for BFM Group (Berlin-Frankfurt-Münster Group); Maria Campbell and Julia Palma for PINDA (Programa Infantil de Drogas Antineoplásicas de Chile); Jan Stary for Czech Republic and ALL-IC; Yves Benoit for EORTC (European Organization for Research and Treatment of Cancer); André Baruchel for FRALLE (French Acute Lymphoblastic Leukaemia Group); Pierre Rohrlich for COOPRALL (Coopération de Traitement des Rechutes de Leucémies Aigues Lymphoblastiques de l’enfant); Isaac Yaniv for ISPHO (Israeli Society for Pediatric Hematology and Oncology); Valentino Conter for AIEOP (Associazione Italiana Ematologia ed Oncologia Pediatrica); Kalman Nagy, Gergely Krivan and Gabor Kovacs for H-POG (Hungary Pediatric Oncology Group); Rob Pieters for DCLSG (Dutch Childhood Leukemia Study Group); Kim Vettenranta for NOPHO (Nordic Society for Pediatric Hematology and Oncology); Keizo Horibe for Japan; Jerzy Kowalczyk for Poland; Nick Goulden and Ajay Vora for MRC-ALL WP (Medical Research Council, Acute Lymphoblastic Leukaemia Working Party; Stephen Hunger for COG (Children’s Oncology Group); Stephen Sallan for Dana Farber.

References 1. Spix C, Eletr D, Blettner M, Kaatsch P (2008) Temporal trends in the incidence rate of childhood cancer in Germany 1987–2004. Int J Cancer 122(8):1859–67 2. Dalmasso P, Pastore G, Zuccolo L, Maule MM, Pearce N, Merletti F, Magnani C (2005) Temporal trends in the incidence of childhood leukemia, lymphomas and solid tumors in north-west Italy, 1967–2001. A report of the Childhood Cancer Registry of Piedmont. Haematologica 90(9):1197–1204 3. Linabery AM, Ross JA (2008) Trends in childhood cancer incidence in the U.S. (1992–2004). Cancer 112(2):416–32 4. Pinkel D (1996) Selecting treatment for children with acute lymphoblastic leukemia. J Clin Oncol 14(1):4–6 5. Pui C-H, Schrappe M, Masera G et  al (2004) Ponte di Legno Working Group: statement on the right of children with leukemia to have full access to essential treatment and report on the Sixth International Childhood Acute Lymphoblastic Leukemia Workshop. Leukemia 18(6):1043–1053 6. Tzortzatou-Stathopoulou F, Papadopoulou AL, Moschovi M et  al (2001) Low relapse rate in children with acute lymphoblastic leukemia after risk-directed therapy. J Pediatr Hematol Oncol 23(9):591–597 Review 7. Schrappe M, Reiter A, Ludwing WD et al (2000) Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95(11):3310–3322 8. Schrappe M, Reiter A, Zimmermann M et  al (2000) Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. Leukemia 14(12):2205–2222 9. Borowitz MJ, Devidas M, Hunger SP et  al (2008) Children’s Oncology Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 111(12):5477–5485 10. Chessells JM (2000) The management of high-risk lymphoblastic leukaemia in children. Br J Haematol 108(2):204–16 Review

251

252 

A. Balduzzi et al. 11. Eden OB (1999) Acute lymphoblastic leukaemia: whom and when should we transplant? Pediatr Transplant 3(Suppl 1):108–15 12. Chessells JM, Bailey C, Richards SM (1995) Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia. Lancet 345(8943):143–8 13. Eden OB (2000) Therapeutic trials in childhood ALL: what’s their future? J Clin Pathol 53(1):55–9 14. Davies SM, Ramsay NK, Klein JP et  al (2000) Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol 18(2):340–7 15. Borgmann A, Zinn C, Hartmann R et  al (2008) Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer 44(2):257–68 16. Metha PA, Davies SM (2008) Allogeneic transplantation for childhood ALL. Bone Marrow Transplant 41(2):133–9 17. Rocha V, Locatelli F (2008) Searching for alternative hematopoietic stem cell donors for pediatric patients. Bone Marrow Transplant 41(2):207–14 18. Petersdorf EW (2004) HLA matching in allogeneic stem cell transplantation. Curr Opin Hematol 11(6):386–91 Review 19. Peters C, Schrauder A, Schrappe M, von Stackelberg A, Stary J, Yaniv I, Gadner H, Klingebiel T, BFM Study Group, the IBFM-Study Group and the Paediatric Disease Working Party of the EBMT (2005) Allogeneic haematopoietic stem cell transplantation in children with acute lymphoblastic leukaemia: the BFM/IBFM/ EBMT concepts. Bone Marrow Transplant 35(Suppl 1):S9–S11 20. Smith M, Arthur D, Camitta B et al (1996) Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14(1):18–24 21. Kosaka Y, Koh K, Kinukawa N et al (2004) Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104(12):3527–34 22. Sallan SE (2006) Myths and lessons from the adult/pediatric interface in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 128–132. Review 23. Barry E, DeAngelo DJ, Neuberg D et al (2007) Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin Oncol 25(7):813–9 24. Chessells JM, Harrison CJ, Watson SL et  al (2002) Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987–1999. Br J Haematol 117(2):306–14 25. Isoyama K, Eguchi M, Hibi S et al (2002) Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96). Br J Haematol 118(4):999–1010 26. Biondi A, Rizzari C, Valsecchi MG et al (2006) Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies. Haematologica 91(4):534–7 27. Jansen MW, Corral L, van der Velden VH et al (2007) Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia 21(4):633–41 28. Pieters R, Schrappe M, De Lorenzo P et al (2007) A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370(9583):240–50 29. Tauchi H, Tomizawa D, Eguchi M et al (2008) Clinical features and outcome of MLL gene rearranged acute lymphoblastic leukemia in infants with additional chromosomal abnormalities other than 11q23 translocation. Leuk Res 32(10):1523–9

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation  30. Tomizawa D, Koh K, Sato T et al (2007) Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study G. Leukemia 21(11):2258–63 31. Aricò M, Ziino O, Valsecchi MG, Cazzaniga G, Baronci C, Messina C, Pession A, Santoro N, Basso G, Conter V, the Italian Association of Pediatric Hematology and Oncology (AIEOP) (2008) Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 113(3):515–21 32. Whitlock JA, Sather HN, Gaynon P, Robison LL, Wells RJ, Trigg M, Heerema NA, Bhatia S (2005) Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 106(13):4043–9 33. Meissner B, Borkhardt A, Dilloo D et al (2007) Relapse, not regimen-related toxicity, was the major cause of treatment failure in 11 children with Down syndrome undergoing haematopoietic stem cell transplantation for acute leukaemia. Bone Marrow Transplant 40(10):945–9 34. Whitlock JA, Sather HN, Gaynon P et  al (2005) Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 106(13):4043–9 35. Chessells JM, Harrison G, Richards SM et al (2001) Down’s syndrome and acute lymphoblastic leukaemia: clinical features and response to treatment. Arch Dis Child 85(4):321–5 36. Schultz KR, Pullen DJ, Sather HN et al (2007) Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood 109(3):926–35 37. Mussolin L, Pillon M, Conter V et al (2007) Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood. J Clin Oncol 25(33):5254–61 38. Attias D, Weitzman S (2008) The efficacy of rituximab in high-grade pediatric B-cell lymphoma/leukemia: a review of available evidence. Curr Opin Pediatr 20(1):17–22 39. Schrauder A, Reiter A, Gadner H et  al (2006) Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol 24(36):5742–9 40. Jones LK, Saha V (2005) Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 130(4):489–500 41. Aricò M, Valsecchi MG, Camitta B et al (2000) Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342(14):998–1006 42. Roy A, Bradburn M, Moorman AV et  al (2005) Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial. Br J Haematol 129(1):35–44 43. Balduzzi A, Valsecchi MG, Uderzo C et al (2005) Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366(9486):635–42 44. Talano JM, Casper JT, Camitta BM et  al (2006) Alternative donor bone marrow transplant for children with Philadelphia chromosome ALL. Bone Marrow Transplant 37(2):135–41 45. Mann G, Cazzaniga G, van der Velden VH et al (2007) Acute lymphoblastic leukemia with t(4;11) in children 1 year and older: The ‘big sister’ of the infant disease? Leukemia 21(4):642–6

253

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A. Balduzzi et al. 46. Nachman J, Sather HN, Gaynon PS et  al (1997) Augmented Berlin-FrankfurtMunster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children’s Cancer Group. J Clin Oncol 15(6):2222–30 47. Aricò M, Valsecchi MG, Conter V et  al (2002) Improved outcome in high-risk childhood acute lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin-Frankfurt-Muenster protocol II. Blood 100(2):420–6 48. Coustan-Smith E, Gajjar A, Hijiya N et al (2004) Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia 18:499–504 49. Eckert C, Biondi A, Seeger K et al (2001) Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 358(9289):1239–41 50. van der Velden VH, Panzer-Grümayer ER, Cazzaniga G et al (2007) Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting. Leukemia 21(4):706–13 51. van der Velden VH, Cazzaniga G, Schrauder A et al (2007) Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia 21(4):604–11 52. Flohr T, Schrauder A, Cazzaniga G et al (2008) Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphobl. Leukemia 22(4):771–82 53. Flotho C, Coustan-Smith E, Pei D et al (2007) A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukaemia. Blood 110:1271–1277 54. Satwani P, Sather H, Ozkaynak F et al (2007) Allogeneic bone marrow transplantation in first remission for children with ultra-high-risk features of acute lymphoblastic leukemia: a Children’s Oncology Group study report. Biol Blood Marrow Transplant 13(2):218–27 55. Sanders JE, Im HJ, Hoffmeister PA et  al (2005) Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Blood 105(9): 3749–56 56. Chessells JM, Richards SM, Bailey CC et al (1995) Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol 89(2):364–72 57. Silverman LB, Gelber RD, Dalton VK et al (2001) Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91–01. Blood 97(5):1211–8 58. Conter V, Aricò M, Valsecchi MG et  al (1998) Intensive BFM chemotherapy for childhood ALL: interim analysis of the AIEOP-ALL 91 study. Associazione Italiana Ematologia Oncologia Pediatrica. Haematologica 83(9):791–9 59. Gaynon PS, Steinherz PG, Bleyer WA et al (1993) Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106. J Clin Oncol 11(11):2234–42 60. Schrappe M, Aricò M, Harbott J et  al (1998) Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92(8):2730–4 61. Uckun FM, Nachman JB, Sather HN et  al (1998) Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children’s Cancer Group. Cancer 83(9):2030–9 62. Nachman JB, Sather HN, Sensel MG et al (1998) Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338(23):1663–71

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation  63. Moorman AV, Richards SM, Robinson HM, Strefford JC, Gibson BE, Kinsey SE, Eden TO, Vora AJ, Mitchell CD, Harrison CJ, UK Medical Research Council (MRC)/National Cancer Research Institute (NCRI) Childhood Leukaemia Working Party (CLWP) (2007) Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood 109(6):2327–30 64. Saarinen UM, Mellander L, Nysom K et  al (1996) Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: a retrospective case-control study in the Nordic countries. Nordic Society for Pediatric Hematology and Oncology (NOPHO). Bone Marrow Transplant 17(3):357–63 65. Wheeler KA, Richards SM, Bailey CC et al (2000) Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI. Blood 96(7):2412–8 66. Gray R, Wheatley K (1991) How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant 7(Suppl 3):9–12 Review 67. Ribera JM, Ortega JJ, Oriol A et al (2007) Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol 25(1):16–24 68. Iori AP, Arcese W, Milano F et  al (2007) Unrelated cord blood transplant in children with high-risk acute lymphoblastic leukemia: a long-term follow-up. Haematologica 92(8):1051–8 69. Locatelli F, Zecca M, Messina C et  al (2002) Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors. Leukemia 16(11):2228–37 70. Bunin N, Carston M, Wall D et al (2002) Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood 99(9):3151–7 71. Dini G, Valsecchi MG, Micalizzi C et al (2003) Impact of marrow unrelated donor search duration on outcome of children with acute lymphoblastic leukemia in second remission. Bone Marrow Transplant 32(3):325–31 72. Tsurusawa M, Yumura-Yagi K, Ohara A et  al (2007) Survival outcome after the first central nervous system relapse in children with acute lymphoblastic leukemia: a retrospective analysis of 79 patients in a joint program involving the experience of three Japanese study groups. Int J Hematol 85(1):36–40 73. Bleakley M, Shaw PJ, Nielsen JM (2002) Allogeneic bone marrow transplantation for childhood relapsed acute lymphoblastic leukemia: comparison of outcome in patients with and without a matched family donor. Bone Marrow Transplant 30(1):1–7 74. Willemze AJ, Geskus RB, Noordijk EM et al (2007) HLA-identical haematopoietic stem cell transplantation for acute leukaemia in children: less relapse with higher biologically effective dose of TBI. Bone Marrow Transplant 40(4):319–27 75. Gassas A, Ishaqi MK, Afzal S et al (2008) Outcome of haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia in third complete remission: a vital role for graft-versus-host-disease/ graft-versus-leukaemia effect in survival. Br J Haematol 140(1):86–9 76. Afify Z, Hunt L, Green A et al (2005) Factors affecting the outcome of stem cell transplantation from unrelated donors for childhood acute lymphoblastic leukemia in third remission. Bone Marrow Transplant 35(11):1041–7 77. Woolfrey AE, Anasetti C, Storer B et al (2002) Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood 99(6):2002–8 78. Sedláček P, Formanková R, Keslová P et al (2006) Low mortality of children undergoing hematopoietic stem cell transplantation from 7 to 8/10 human leukocyte

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A. Balduzzi et al. antigen allele-matched unrelated donors with the use of antithymocyte globulin. Bone Marrow Transplant 38(11):745–50 79. Al-Kasim FA, Thornley I, Rolland M et  al (2002) Single-centre experience with allogeneic bone marrow transplantation for acute lymphoblastic leukaemia in childhood: similar survival after matched-related and matched-unrelated donor transplants. Br J Haematol 116(2):483–90 80. Gassas A, Sung L, Saunders EF et al (2007) Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations. Bone Marrow Transplant 40(10):951–5 81. Eapen M, Rubinstein P, Zhang MJ et  al (2007) Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369(9577):1947–54 82. Sanders JE, Guthrie KA, Hoffmeister PA et  al (2005) Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood 105(3):1348–54 83. Houtenbos I, Bracho F, Davenport V et  al (2001) Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia: a novel combined approach consisting of ex vivo marrow purging, modulation of multi-drug resistance, induction of autograft vs leukemia effect, and post-transplant immuno- and chemotherapy (PTIC). Bone Marrow Transplant 27(2):145–53 84. Balduzzi A, Conter V, Uderzo C, Valsecchi MG (2007) Transplantation in childhood very high risk acute lymphoblastic leukemia in first complete remission: where are we now? J Clin Oncol 25(18):2625–6 85. Gustafsson Jernberg A, Remberger M, Ringdén O et al (2004) Risk factors in pediatric stem cell transplantation for leukaemia. Pediatr Transplant 8(5):464–74 86. Balduzzi A, De Lorenzo P, Schrauder A, Conter V, Uderzo C, Peters C, Klingebiel T, Stary J, Felice MS, Magyarosy E, Schrappe M, Dini G, Gadner H, Valsecchi MG (2008) Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time. Haematologica 93:925–929 87. Gratwohl A, Baldomero H, Frauendorfer K et al (2007) Results of the EBMT activity survey 2005 on haematopoietic stem cell transplantation: focus on increasing use of unrelated donors. Bone Marrow Transplant 39(2):71–87 88. Eapen M, Rubinstein P, Zhang MJ et  al (2006) Comparable long-term survival after unrelated and HLA-matched sibling donor hematopoietic stem cell transplantations for acute leukemia in children younger than 18 months. J Clin Oncol 24(1):145–51 89. Quaranta BP, Halperin EC, Kurtzberg J et  al (2004) The incidence of testicular recurrence in boys with acute leukemia treated with total body and testicular irradiation and stem cell transplantation. Cancer 101(4):845–50 90. Malempati S, Gaynon PS, Sather H et al (2007) Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children’s Oncology Group study CCG-1952. J Clin Oncol 25(36):5800–7 91. Lawson SE, Harrison G, Richards S et  al (2000) The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol 108(3):531–43 92. Chessells JM, Veys P, Kempski H et  al (2003) Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 123(3):396–405 93. Rizzari C, Valsecchi MG, Aricò M et  al (2004) Outcome of very late relapse in children with acute lymphoblastic leukemia. Haematologica 89(4):427–34 94. Roy A, Cargill A, Love S et  al (2005) Outcome after first relapse in childhood acute lymphoblastic leukaemia – lessons from the United Kingdom R2 trial. Br J Haematol 130(1):67–75

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation    95. Einsiedel HG, von Stackelberg A, Hartmann R et al (2005) Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87. J Clin Oncol 23(31):7942–50   96. Eapen M, Zhang MJ, Devidas M et  al (2008) Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research. Leukemia 22(2):281–6   97. Eapen M, Raetz E, Zhang MJ, Muehlenbein C, Devidas M, Abshire T, Billett A, Homans A, Camitta B, Carroll WL, Davies SM (2006) Outcomes after HLAmatched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 107(12):4961–7   98. Gaynon PS, Harris RE, Altman AJ et al (2006) Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children’s Oncology Group study CCG. J Clin Oncol 24(19):3150–6   99. Dopfer R, Henze G, Bender-Götze C et  al (1991) Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALLprotocols: results of the German Cooperative Study. Blood 78(10):2780–4 100. Borgmann A, von Stackelberg A, Hartmann R et  al (2003) Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood 101(10):3835–9 101. Harrison G, Richards S, Lawson S et al (2000) Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party. Ann Oncol 11(8):999–1006 102. von Stackelberg A, Hartmann R, Bührer C et al (2008) High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood 111(5):2573–80 103. Wheeler K, Richards S, Bailey C, Chessells J (1998) Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia. Br J Haematol 101(1):94–103 104. Bader P, Hancock J, Kreyenberg H (2002) Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for posttransplant outcome in children with ALL. Leukemia 16(9):1668–72 105. Goulden N, Bader P, Van Der Velden V et  al (2003) Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia. Br J Haematol 122(1):24–9 106. Knechtli CJ, Goulden NJ, Hancock JP et al (1998) Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia. Blood 92(11):4072–9 107. Krejci O, van der Velden VH, Bader P et  al (2003) Level of minimal residual disease prior to haematopoietic stem cell transplantation predicts prognosis in paediatric patients with acute lymphoblastic leukaemia: a report of the Pre-BMT MRD Study Group. Bone Marrow Transplant 32(8):849–51 108. Dufourg MN, Landman-Parker J, Auclerc MF et  al (2007) Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children. Leukemia 21(2):238–47

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A. Balduzzi et al. 109. Jansen NC, Kingma A, Schuitema A et al (2006) Post-treatment intellectual functioning in children treated for acute lymphoblastic leukaemia (ALL) with chemotherapy-only: a prospective, sibling-controlled study. Eur J Cancer 42(16):2765–72 110. Krappmann P, Paulides M, Stöhr W et al (2007) Almost normal cognitive function in patients during therapy for childhood acute lymphoblastic leukemia without cranial irradiation according to ALL-BFM 95 and COALL 06–97 protocols: results of an Austrian-German multicenter longitudinal study and implications for follow-up. Pediatr Hematol Oncol 24(2):101–9 111. Waber DP, Turek J, Catania L et  al (2007) Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J Clin Oncol 25(31):4914–21 112. Matsuzaki A, Nagatoshi Y, Inada H et al (2005) Prognostic factors for relapsed childhood acute lymphoblastic leukemia: impact of allogeneic stem cell transplantation – a report from the Kyushu-Yamaguchi Children’s Cancer Study Group. Pediatr Blood Cancer 45(2):111–20 113. Borgmann A, Baumgarten E, Schmid H et  al (1997) Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative? Bone Marrow Transplant 20(11):939–44 114. Blair A, Goulden NJ, Libri NA et al (2005) Immunotherapeutic strategies in acute lymphoblastic leukaemia relapsing after stem cell transplantation. Blood Rev 19(6):289–300 115. Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza FR Jr, Ringdén O, Wagner JE (2004) Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 22(24):4872–80 116. Marks DI, Khattry N, Cummins M et al (2006) Haploidentical stem cell transplantation for children with acute leukaemia. Br J Haematol 134(2):196–201 117. Ishaqi MK, Afzal S, Dupuis A et  al (2008) Early lymphocyte recovery postallogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia. Bone Marrow Transplant 41(3):245–52 118. Rocha V, Michel G, Kabbara N, et al (2005) Outcomes after unrelated cord blood transplantation in children with acute lymphoblastic leukemia. An EurocordNetcord survey. Blood abstract# 304, page 93a. 119. Rocha V, Cornish J, Sievers E, Filipovich A, Locatelli F, Peters C et  al (2001) Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 97:2962–2971 120. Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE (2001) Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. Blood 97:2957–2961 121. Dalle JH, Duval M, Moghrabi A, Wagner JE, Vachon MF, Barrette S et al (2004) Results of an unrelated transplant search strategy using partially HLA-mismatched cord blood as an immediate alternative to HLA-matched bone marrow. Bone Marrow Transplant 33:605–11 122. Hwang WY, Samuel M, Tan D, Koh LP, Lim W, Linn YC (2007) A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients. Biol Blood Marrow Transplant 13:444–53 123. Rocha V, Gluckman E (2007) Outcomes of transplantation in children with acute leukaemia. Lancet 369(9577):1906–8

Chapter 15  Allogeneic Hematopoietic Stem Cell Transplantation  124. Hough R, Labopin M, Michel G, Locatelli F, Klingebiel T, Arcese W et al (2007) Outcomes of fully haplo-identical haematopoietic stem cell transplantation compared to unrelated cord blood transplantation in children with acute lymphoblastic leukaemia. A retrospective analysis on behalf of Eurocord, PDWP and ALWP of EBMT. Bone Marrow Transplant 39(S1):S3 125. Bunin N, Aplenc R, Kamani N et al (2003) Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant 32(6):543–8 126. Jamieson CH, Amylon MD, Wong RM et al (2003) Allogeneic hematopoietic cell transplantation for patients with high-risk acute lymphoblastic leukemia in first or second complete remission using fractionated total-body irradiation and high-dose etoposide: a 15-year experience. Exp Hematol 31(10):981–6 127. Marks DI, Forman SJ, Blume KG et al (2006) A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant 12(4):438–53 128. Ringdén O, Ruutu T, Remberger M et  al (1994) A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood 83(9):2723–30 129. Zecca M, Pession A, Messina C, Bonetti F, Favre C, Prete A, Cesaro S, Porta F, Mazzarino I, Georgiani G, Rondelli R, Locatelli F (1999) Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings. J Clin Oncol 17(6):1838–1846 130. Iravani M, Evazi MR, Mousavi SA et  al (2007) Fludarabine and busulfan as a myeloablative conditioning regimen for allogeneic stem cell transplantation in high- and standard-risk leukemic patients. Bone Marrow Transplant 40(2):105–10 131. Brydøy M, Fosså SD, Dahl O et al (2007) Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol 46(4):480–9 132. Chow EJ, Friedman DL, Yasui Y et al (2007) Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Pediatr 150(4):370–5 375 133. Cohen IJ (2007) Comparison of long-term neurocognitive outcomes in young children with acute lymphatic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate. J Clin Oncol 25(6):734–5 134. Löf CM, Forinder U, Winiarski J (2007) Risk factors for lower health-related QoL after allogeneic stem cell transplantation in children. Pediatr Transplant 11(2):145–51 135. Bader P, Niethammer D, Willasch A et al (2005) How and when should we monitor chimerism after allogeneic stem cell transplantation? Bone Marrow Transplant 35(2):107–19 136. Sànchez J, Serrano J, Gòmez P et  al (2002) Clinical value of immunological monitoring of minimal residual disease in acute lymphoblastic leukaemia after allogeneic transplantation. Br J Haematol 116(3):686–94 137. Uzunel M, Jaksch M, Mattsson J et al (2003) Minimal residual disease detection after allogeneic stem cell transplantation is correlated to relapse in patients with acute lymphoblastic leukaemia. Br J Haematol 122(5):788–94 138. Uzunel M, Mattsson J, Jakssch M et al (2001) The significance of graft-versushost disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. Blood 98(6):1982–4

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260 

A. Balduzzi et al. 139. Gadner H, Masera G, Schrappe M et al (2006) The Eighth International Childhood Acute Lymphoblastic Leukemia Workshop (‘Ponte di legno meeting’) report: Vienna, Austria, April 27–28, 2005. Leukemia 20(1):9–17 140. Aricò M, Baruchel A, Bertrand Y et al (2005) The Seventh International Childhood Acute Lymphoblastic Leukemia Workshop report: Palermo, Italy, January 29–30, 2005. Leukemia 19(7):1145–52 141. Saarinen-Pihkala UM, Heilmann C, Winiarski J et  al (2006) Pathways through relapses and deaths of children with acute lymphoblastic leukemia: role of allogeneic stem-cell transplantation in Nordic data. J Clin Oncol 24(36):5750–62 142. Rivera GK, Zhou Y, Hancock ML et  al (2005) Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer 103(2):368–76

Chapter 16 Allogeneic Transplantation for the Treatment of Multiple Myeloma Rebecca L. Olin, Dan T. Vogl, and Edward A. Stadtmauer

1. Introduction Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of plasma cells. The annual incidence is four per 100,000 individuals. It was estimated that 19,900 new cases would be diagnosed in 2007, with 10,790 estimated deaths due to myeloma [1]. The median age at diagnosis is approximately 65 years, making it a disease that predominantly affects older patients. Although myeloma cells are chemosensitive, the median survival for patients with multiple myeloma remains less than 5 years. Melphalan and prednisone remain the chemotherapeutic agents of choice for older patients who are not transplant candidates, because long term outcomes have not shown any improvement with more intensive multi-agent chemotherapy regimens [2, 3]. The addition of novel agents such as thalidomide, bortezomib, and lenalidomide to melphalan and steroids may improve outcomes in this group of patients [4, 5]. The current standard of care for younger eligible patients is initial conventional dose therapy followed by high-dose melphalan and autologous hematopoietic stem cell transplant. Two randomized and several nonrandomized comparative studies show improved survival with transplant over standard chemotherapy [6, 7]. Recent investigations have shown promising results with tandem autologous transplants and incorporation of the newer agents into the first line of therapy. Unfortunately, despite these advances, almost all patients will ultimately relapse. Allogeneic transplantation is the only modality to have demonstrated curative potential in multiple myeloma. Early studies of allogeneic transplants for myeloma resulted in a small number of long-term survivors. Additional studies supported the existence of an immune mediated “graft-versus-myeloma” effect. However, these early studies were plagued by high transplant-related mortality (TRM), even in patients who were not heavily pre-treated. Because of this as well as the advanced age of most myeloma patients and the limited number of available donors, use of allogeneic transplants has been limited.

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_16, © Springer Science + Business Media, LLC 2003, 2010

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The focus of recent research has been to determine ways to decrease toxicity of transplantation while still achieving long-term disease control or cure. These studies will be reviewed here.

2. Background of Therapy Currently, multiple myeloma represents the most common indication for autologous stem cell transplantation in North America, with over four thousand transplants performed in 2003 [8]. Initial studies compared patients who received autologous transplants to historical controls and suggested that survival was prolonged [9, 10]. Subsequently, two prospective randomized trials have shown a survival advantage for autologous transplant over standard chemotherapy. In the French IFM study, 200 previously untreated patients were randomly assigned conventional chemotherapy or high-dose therapy with melphalan and total body irradiation (TBI) [6]. Overall response rates, progression-free survival (PFS), and overall survival (OS) were all significantly improved; the 5 year OS for patients receiving autologous transplant was 52 vs. 12% for conventional chemotherapy. The British MRC VII study, randomized 407 patients to conventional therapy or autologous transplantation using high-dose melphalan [7]. Median survival was extended from 42 months with chemotherapy to 54 months with transplantation. Some comparative trials have not shown a survival advantage for transplant over conventional chemotherapy [11–13]. These usually allowed for transplant at time of relapse for conventional dose treatment failures or the use of more toxic preparative regimens [14]. Given the palliative goal of autologous transplant, either an approach of initial cytoreduction followed by autologous transplant or use of transplant at time of first progression has become the common alternative. Recent studies have reported tandem autologous transplants as part of initial therapy for myeloma. The IFM94 randomized trial demonstrated an improved median OS with tandem autologous transplants when compared to a single transplant [15]; 7- year survival was 43% in the group randomized to tandem transplants vs. 11% in the single transplant group. A subgroup analysis suggested that the survival benefit was limited to the group of patients with a less than 90% disease response after the first transplant. Other studies have not confirmed this finding [16, 17]. In addition to high-dose melphalan and autologous stem cell transplantation, the outcomes of treatment for multiple myeloma have been improved by novel agents such as thalidomide, lenalidomide, and bortezomib [18]. Incorporation of these agents into both upfront, maintenance, and salvage therapy programs is currently under active investigation, but no study has yet shown the superiority of nontransplant approaches.

3. Rationale for Allogeneic Transplantation The anti-tumor effect of allogeneic transplantation results from administration of high doses of chemotherapy and radiation as well as an immune-mediated graft-versus-tumor effect in which donor immune cells recognize and eradicate residual disease. Clinical evidence, both direct and indirect, suggests that a true graft-versus-myeloma effect exists. Case reports have shown that for

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myeloma relapsing after allogeneic transplant, remission can be reestablished by withdrawing immunosuppression [19]. A number of reports also showed that donor lymphocyte infusion (DLI) could also result in clinical responses and achievement of prolonged remissions; [20–23] subsequent larger studies demonstrated the effectiveness of this approach [24, 25]. Withdrawal of immunosuppression and DLI have become accepted strategies for relapse or residual disease after allogeneic transplantation, in order to harness the graftversus-myeloma effect and induce disease responses. Finally, response to DLI has correlated with the development of acute and/or chronic graft-versus-host disease (GVHD) [25–27], suggesting that both are due to the immune activity of the donor cells.

4. Myeloablative Allogeneic Transplantation 4.1. Results: Transplant-Related Mortality and Overall Survival Most data for the use of allogeneic transplantation in multiple myeloma come from single-center trials and registry databases. Although heterogeneity among the trials limits comparisons, early studies of allogeneic transplant (performed in the 1980s and early 1990s) demonstrated high TRM but subsequent plateau of survival curves, with corresponding small but encouraging numbers of long-term disease-free survivors. Later studies have demonstrated somewhat lower TRM, which is thought to be due to decreased infection rates and earlier transplantation with less prior chemotherapy (Table 16-1). In 1991, Gahrton et  al. reported European registry data (EBMT) for 90 patients who received an allogeneic transplant between 1983 and 1989 from HLA-identical siblings [28]. Preparative regimens varied but the majority received cyclophosphamide/TBI (Cy/TBI) or melphalan/TBI (Mel/TBI). The overall complete response rate was 43%, and survival at 76 months was 40%. TRM, however, was 25%, due to GVHD, infections, and pneumonitis. The number of prior lines of treatment was inversely related to complete remission (CR). In a later review of EBMT data, median survival after allogeneic transplant was reported to be only 1.5 years and TRM approached 50% [29]. The long-term survival rate was 30%, and the relapse rate approached 70%, with

Table 16-1.  Major reports of myeloablative transplantation. Author

Source data

Dates of transplants

N

TRM (%)

OS

Gahrton [28]

EBMT

1983–1989

   90

25

40% (6.3 years)

Bjorkstrand [29]

EBMT

1983–2001

1,300+

50

Median 1.5 years

Bensinger [30]

Seattle

1987–1994

   80

57

24% (4.5 years)

Bensinger [31]

Seattle

1987–1999

  136

48

22% (5 years)

Barlogie [14]

Intergroup trial

1993–1994

   36

53

39% (7 years)

Gahrton [40]

EBMT

1983–1993

  334

46

40% (2 years), median 10 months

1994–1998

  356

30

57% (2 years), median 50 months

N number of patients, TRM transplant-related mortality, OS overall survival

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relapses occurring many years after transplantation. The TRM approached 50%, making allogeneic transplantation unattractive. The three-arm Intergroup trial S9321 compared early to late autotransplants and offered allogeneic transplants to patients who were younger than 56 years and had an HLA-identical sibling donor. The allogeneic arm of this trial was closed when a first-year TRM of 53% was observed after 36 eligible patients were enrolled [14]. The largest single-center published experience with allogeneic transplants for myeloma is from Seattle. In 1996, investigators there reported 80 patients who received transplants primarily from HLA-identical siblings between 1987 and 1994 [30]. The conditioning regimen used was busulfan/cyclophosphamide (Bu/Cy) with or without TBI. The CR rate was 36%, and actuarial survival was 20% at 4.5 years. Again, TRM was high at 57%, with 44% occurring in the first 100 days. Updated data published in 2001 for 136 patients again revealed a high TRM of 48% in the first 100 days [31]. However, OS was 22% at 5 years, and 12 patients remain alive and free of disease between 5 and 13 years post-transplant. Other early single-center reports have shown similar results [32–39]. Improvements in supportive care and GVHD prophylaxis may lead to reduced TRM in the current era. In 2001, an analysis of EBMT registry data was published comparing allogeneic transplants performed for multiple myeloma between 1983 and 1993 with those performed between 1994 and 1998 [40]. There was a highly significant difference between these two groups, with median OS of 10 months for patients transplanted in the earlier period, compared with 50 months for the later period. The improvement in survival was shown to be due to a reduction in TRM, which was 46% and 30% at 2 years for the early and late period, respectively. Significantly fewer cases of infections and interstitial pneumonitis were observed in the later group, and transplants were also performed sooner after diagnosis; rates of GVHD were similar. Indeed, single- and multi-center studies of allogeneic transplants performed in the 1990s do seem to support a somewhat lower TRM [41–51], the majority reporting a TRM in the range of 20–30%. 4.2. Comparison with Autologous Transplantation The relative benefits of autologous and allogeneic transplantation for multiple myeloma have been compared in several studies. (Table  16-2) The EBMT registry reported 189 patients who received allogeneic transplants compared to 189 case-matched controls who received autologous transplants [52]. Cases were matched for gender and for number of prior lines of treatment; 60% had at least two prior treatments. Median survival was significantly shorter for allogeneic transplant than autologous (18 vs. 34 months). This effect was consistent in all subgroups analyzed, and was due mainly to a difference in TRM, which was 41% for allogeneic and 13% for autologous transplants. When the data were analyzed using only those patients who survived >1 year, however, there was a trend toward improved survival in the allogeneic arm, with significantly longer PFS. Single-center studies have reported similar findings. Couban et  al. found that allogeneic transplantation, when compared to autologous, resulted in a higher 90-day mortality (27 vs. 5%), with a slightly improved 3-year PFS

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma 

265

Table 16-2.  Comparisons of allogeneic and autologous transplantation. Author

N

TRM (%)

PFS

OS

Bjorkstrand [52]

189 allo 189 auto

41* 13

Median 11 m† Median 20 m

Median 18 m* Median 34 m

Couban [33]

22 allo 40 auto

27 (90d)† 5 (90d)

22% 3 year† 17% 3 year

32% 3 year† 74% 3 year

Alyea [43]

66 allo 166 auto

24* 13

28% 2 year*, 18% 4 year 48% 2 year, 23% 4y

51% 2 year*, 39% 4 year 74% 2 year, 41% 4 year

Arora [48]

17 allo 70 auto

18 (100d)* 4 (100d)

58% 1 year, 32% 4 year 67% 1 year, 18% 4 year

64% 1 year, 64% 4 year 86% 1 year, 50% 4 year

Mehta [37]

42 allo 42 auto

43* 10

20% 3 year 25% 3 year

29% 3 year* 54% 3 year

Reynolds [42]

21 allo 35 auto

19 (100d) 9 (100d)

60% 2 year 30% 2 year

60% 2 year 42% 2 year

Kuruvilla [51]

72 allo 86 auto

22 14

33% 5 year, 31% 10 year 33% 5 year, 15% 10 year

48% 5 year, 40% 10 year 46% 5 year, 31% 10 year

N number of patients, TRM transplant-related mortality, PFS progression-free survival, OS overall survival. *Statistically different from autologous group. †Statistical significance not reported

(22 vs. 17%), but markedly worse 3-year OS (32 vs. 74%) [33]. Alyea et al. reported that at 2 years, OS was 51% for allogeneic vs. 74% for autologous transplantation, but by 4 years, OS was similar at 39 vs. 41% [43]. Relapses were less frequent in the allogeneic group; however, nonrelapse mortality was significantly higher. Arora et  al. also demonstrated that allogeneic transplant result in a higher TRM, but lower PFS than autologous transplant [48]. The survival curves crossed, with OS higher for autologous than for allogeneic transplant at 1 year (64 vs. 86%), but lower at 4 years (64 vs. 50%). Mehta et  al. compared 42 patients who received a salvage allogeneic transplant after a first autograft with 42 matched patients receiving a salvage autologous transplant [37]. Three-year survival was significantly lower after allogeneic transplant (29 vs. 54%), because of higher TRM (43 vs. 10%). Reynolds et  al. who controlled for treatment regimen by performing both allogeneic and autologous transplants with the same conditioning regimen of Bu/Cy/TBI, found no statistically significant difference in PFS (60 vs. 30% at 2 years) or OS (60 vs. 42%), although there was a trend toward improved outcomes in the allogeneic group [42]. Finally, Kuruvilla et al. recently reported 7-year follow-up data on 72 allogeneic and 86 autologous transplants; the estimated 10-year OS was 40 vs. 30% respectively, which was not significantly different [51]. As a group, these studies indicate that allogeneic transplantation results in higher TRM than autologous transplantation, although typically with decreased relapse rates and longer PFS. These factors exert opposite effects on OS, resulting in inferior OS soon after transplant and potentially similar or improved OS after longer follow-up. Interestingly, in the Intergroup study

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S9321, despite early closure of the allogeneic arm due to high TRM, the survival curve did subsequently plateau, indicating a fraction of patients possibly cured and resulting in similar 6-year PFS and OS for the allogeneic and autologous arms [14, 53]. 4.3. Syngeneic Transplantation Syngeneic transplantation from an identical twin offers the possibility of a tumorfree graft without the risk of GVHD. Bensinger et al. reported 11 patients who received syngeneic transplants using varying conditioning regimens. Two were long-term survivors: one disease-free at 9 years, and other with a persistent serum monoclonal protein 15 years post-transplant [54]. Gahrton et al. used EBMT registry data to compare 25 twin transplants with 125 case-matched patients who underwent autologous transplant and 125 who underwent allogeneic transplant [55]. Median OS and PFS both appeared to be better for syngeneic compared with autologous transplants (OS 73 vs. 44 months and PFS 72 vs. 25 months), though only the difference in PFS was statistically significant. Survival was significantly worse from allogeneic transplants (median survival 16 months); this was mainly due to high TRM. 4.4. Allogeneic Stem Cell Source and Alternative Donors Initial studies of allogeneic transplants utilized bone marrow stem cells (BMSC). More recently investigators have used peripheral blood stem cells (PBSC), which have been shown to decrease time to engraftment in a randomized trial of patients with diverse hematologic malignancies [56]. Majolino et al. demonstrated the feasibility of using PBSC in allogeneic transplants for myeloma in a retrospective analysis of 10 patients [36]. All patients engrafted, and all achieved CR. TRM was 20%, and OS was 80% at a median of 18.5 months of follow-up. In a later analysis of EBMT registry data, PBSC transplants were compared to BMSC transplants done for myeloma between 1994 and 1998 [40]. Use of PBSC was associated with earlier engraftment, but no survival advantage. There was a trend toward increased GVHD with PBSC (18% grade III/IV with PBSC vs. 11% with BMSC), but this was not statistically significant. Ballen et  al. retrospectively analyzed NMDP registry data for 70 patients who received a matched unrelated donor (MUD) allogeneic transplant for myeloma [57]. The 100-day TRM was 42%, and OS at 5 years was quite low at 9%. Survival was not significantly different when stratified for prior autologous transplant or for GVHD. 4.5. T-Cell Depletion GVHD remains the primary source of morbidity and mortality in allogeneic transplantation for multiple myeloma. Published rates of GVHD range from 20 to 80%, with a significant proportion of patients developing grades II–IV acute and chronic GVHD. A number of studies have investigated T-cell depleted grafts, in an attempt to decrease this toxicity. In a prospective study, Lokhorst et  al. treated 53 patients with multiple myeloma with allogeneic grafts that were partially T-cell depleted [46]. Cy/TBI conditioning was used for the majority of patients. Grade II–IV acute GVHD (aGVHD) was seen in 45%, and extensive chronic GVHD (cGVHD) in 30%.

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma 

TRM was 34%. The median OS was poor at 25 months, inferior to standard chemotherapy, which suggested loss of the graft-versus-myeloma effect. Using an alternative strategy, Kroger et al. used in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of a conditioning regimen also including Bu/Cy/TBI [45]. Grade II–IV GVHD was seen in 35%, and after a median of 41 months of follow-up, estimated OS at 6 years was 77%. Alyea et  al. utilized the combination of CD6 T-cell depleted grafts with subsequent prophylactic DLI at 6–9 months post-transplant in order to reduce TRM and maintain a graft-versus-myeloma effect [58]. T-cell depletion was the sole method of GVHD prophylaxis. Twenty-four patients were treated; grade II–IV aGVHD was seen in 21% after transplant, and 50% of patients who went on to receive DLI experienced acute or chronic GVHD. The 100day TRM was only 4%; however, estimated 2-year PFS was relatively low at 30%. Similarly, Huff et  al. report on the long-term follow-up of 51 patients who received T-cell depleted allogeneic transplants [44]. Only 14% had grade II–IV aGVHD after transplant, and 6% had cGVHD. However, TRM was 24%, and 31 of 39 patients had disease progression after transplant, suggesting that T-cell depleted grafts may yield lower TRM but also decreased PFS. 4.6. Prognostic Factors Factors predicting a good outcome with allogeneic transplantation are generally similar to those for autologous transplantation. Favorable prognostic factors include only one prior treatment regimen, responding disease at the time of transplant, and low b2-microglobulin at diagnosis [29, 59]. The most important post-transplant prognostic factor is achievement of CR. Gender of both donor and recipient arealso important, with the best OS seen in the combination of female patients with female donors [60]. The Seattle group reported adverse prognostic factors to include transplantation >1 year from diagnosis, b2-microglobulin >2.5 mg/L at transplant, female patient with male donor, >8 cycles of prior chemotherapy, and Durie stage 3 at transplant [30]. In a subsequent report with a larger number of patients, mortality within 100 days was also significantly influenced by pre-transplant serum albumin [31]. Donor gender did not affect PFS, because having a female donor resulted in a lower risk of relapse but also a higher TRM, with these two effects appearing to negate each other.

5. Nonmyeloablative Allogeneic Transplantation 5.1. Phase II Studies Nonmyeloablative allogeneic stem cell transplant to reduce TRM is particularly attractive for myeloma to reduce transplant related mortality. Several phase II studies of nonmyeloablative transplants in patients with myeloma have been reported [61–77]. These studies included between 10 and 120 patients. The most common conditioning regimens used were melphalan/fludarabine, other melphalan-based regimens, other fludarabine-based regimens, or TBIbased combinations. Many of the patients in these studies were very heavily pretreated: most had had at least one prior autograft, and some had many prior lines of therapy. TRM in these studies typically ranged from 0 to 25% with

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100 day post-transplant TRM not exceeding 19%, significantly lower than that for full-intensity allogeneic transplantation. No study reported difficulties with engraftment, and 80–100% of patients achieved full donor chimerism. While nonmyeloablative transplants may result in lower TRM, the risk of GVHD is still high. Rates of both grade II–IV aGVHD as well as cGVHD in phase II studies typically ranged from 30 to 70%. However, the variable GVHD prophylaxis regimens make direct comparison difficult. In a singlecenter study, Pérez-Simón et  al. analyzed 150 nonmyeloablative and 88 myeloablative transplant patients. All patients received the same GVHD prophylaxis and PBSC from an HLA-identical sibling donor [78]. The incidence of grade II–IV aGVHD was 29% for nonmyeloablative vs. 39% for myeloablative transplants, which was statistically significant. In a multivariate analysis, intensity of conditioning was the only variable to influence the incidence of aGVHD. Incidence of cGVHD was not significantly different for nonmyeloablative transplants (71 vs. 63%), although there was a higher incidence of limited, but not extensive, cGVHD. The percentage of patients on immunosuppression at 3 years post-transplant was also lower in the nonmyeloablative group (36 vs. 69%). Estimated PFS after nonmyeloablative transplants ranges from 15 to 50% at 1.5–4 years, and estimated OS ranges from 25 to 70%. Comparing these studies is difficult, however, given small numbers of patients, differences in patient populations, and differences in conditioning regimens. In the largest reported series, Kroger et al. describe 120 patients who received melphalan/fludarabine nonmyeloablative transplants [67]; 38 were done in tandem fashion after autologous transplant, 58 were done for relapse after autologous transplant, and 24 were done after chemotherapy alone. PFS of the entire group was 39% at 2 years, and OS was 59%. In a review of EBMT registry data, Crawley et al. report on 229 patients who received nonmyeloablative transplants; 169 had received at least one prior autograft. PFS was 21% at 3 years, and OS was 41% at 2 years [79]. MUD nonmyeloablative transplants have also been described in a single-center study of 24 patients with poor-risk myeloma; at 3 years, PFS was 33% and OS 61%, with TRM again only 21% [80]. EBMT data was used to compare patients who had received myeloablative allogeneic transplantation (n = 196) with those who had received nonmyeloablative transplants (n = 320) [81]. Patients who received nonmyeloablative transplants were older; they were also more likely to have received a prior autograft and to have progressive disease at the time of allogeneic transplant. TRM at 2 years was 24% for nonmyeloablative and 37% for myeloablative transplants. However, response rates were significantly lower in the nonmyeloablative group (CR in 34 vs. 53%) and PFS was also inferior (19 vs. 35% at 3 years). For this reason, OS was not significantly different between groups (38 vs. 50% at 3 years for nonmyeloablative and myeloablative, respectively). 5.2. Prognostic Factors Pre- and post-transplant prognostic factors have emerged from phase II studies; these have also provided insight into the mechanism of disease control in nonmyeloablative transplants. A number of studies have demonstrated, using multivariate analysis, that the presence of cGVHD after transplant improves both PFS [62, 64, 67, 68, 71, 73] and OS [71, 73]. Interestingly, aGVHD does

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma 

not improve PFS/OS [64], and in some cases may worsen OS via increased TRM [68, 82]. These findings support the theory that the immunologic activity of the graft against myeloma cells, when not associated with the high toxicity of severe GVHD, can reduce the risk of relapse and prolong survival. A pre-transplant prognostic factor, which has been shown to influence PFS and OS, is the presence of chemosensitive disease prior to nonmyeloablative transplant or, similarly, achievement of CR prior to transplant [62, 68, 79, 82]. Many studies have also shown that outcomes are improved if nonmyeloablative transplant is performed earlier in the course of disease treatment; this adverse prognostic factor has been expressed as >1 prior autologous transplant [61, 79], high number of prior cycles of chemotherapy [64, 83], prior relapse after an autograft [66, 67, 76], or a longer interval between prior autograft and nonmyeloablative transplant [73]. By contrast, when nonmyeloablative transplant was studied specifically as salvage therapy for relapse after prior autologous transplant, a shorter interval between transplants was shown to be an adverse prognostic factor [84]; however, this is likely an indicator of underlying chemoresistant disease. Additional adverse prognostic factors include chromosome arm 13q deletion [83] and the persistence of cytogenetic abnormalities after nonmyeloablative transplant [85]. 5.3. Tandem Autologous-Nonmyeloablative Transplantation The high relapse rate after nonmyeloablative allogeneic transplant for myeloma appears to be in part due to the inability of the graft vs. myeloma effect to eradicate a large burden of chemotherapy resistant disease. Outcomes from nonmyeloablative transplantation seem to be improved when carried out early in the course of myeloma treatment and a strategy of tandem autologous transplant followed by nonmyeloablative allogeneic transplant has been explored. This strategy pairs the cytoreductive effect of an autologous transplant with the immunologic benefits of a nonmyeloablative allogeneic transplant. A number of phase II studies have been performed using this approach [86–90]. TRM in these studies ranges from 0 to 20%, similar or lower than in studies of nonmyeloablative transplant alone in more heavily pretreated patients. The rates of acute and chronic GVHD are similar to those seen after nonmyeloablative transplant alone, ranging from 25 to 65%. PFS is approximately 50–60% at 2–3 years, and OS is 60–80% (Table 16-3; Fig. 16-1). Most notably, this approach has been tested in two randomized trials, with conflicting results. In 2000, the French IFM group began enrolling high- risk myeloma patients into one of two trials [91]. If an HLA-identical sibling were available, patients were offered tandem autologous-nonmyeloablative transplants (IFM 99-03, n = 65; melphalan 200 mg/m2 followed by fludarabine/ busulfan/ATG, with cyclosporine/methotrexate for GVHD prophylaxis). If patients did not have an HLA-identical sibling, they were offered tandem autologous transplants (IFM 99-04, n = 219; melphalan 200  mg/m2 followed by melphalan 220 mg/m2, dexamethasone, +/− anti-IL-6 monoclonal antibody). The results of these separate trials were then compared. Some selection bias was inevitable. Although patients were biologically assigned by the presence or absence of an HLA-identical sibling, 24 patients in the autologous study were not HLA typed. The two groups were also demographically different: patients in the autologous study were older (median age 58 vs. 54 years;

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Table 16-3.  Tandem autologous-nonmyeloablative transplantation Author

N

Nonmyeloablative regimen

TRM (%)

GVHD (% acute grades II-IV/% chronic)

Carella [86]

16

Flu/TBI

 6

43/55

62% 3 year

Galimberti [87]

20

Flu/Cy, Flu/TBI

20

45/30

58% 2 year

Kroger [88]

17

Mel/Flu/ATG

11 (100d)

38/40

74% 2 year

Maloney [89]

54

TBI

15

38/46

78% 2 year

Seok [90]

12

Mel/Flu

 0

33/50

100% with median 15 m follow-up

Garban [91]

65 auto-allo

Flu/Bu/ATG

11

24/43

Median 35 m

219 auto-auto

–

 5

–

Median 41 m

80 auto-allo

TBI

10

43/64

Median 80 m*

82 auto-auto

–

 2

–

Median 54 m

Bruno [92]

OS

N number of patients, TRM transplant-related mortality, GVHD graft-versus-host-disease, OS overall survival, Mel melphalan, Flu fludarabine, ATG anti-thymocyte globulin, TBI total body irradiation, Cy cyclophosphamide. *Statistically significant from autologous group

Fig. 16.1.  Cumulative incidence of acute and chronic GVHD after sequential autologousnonmyeloablative transplantation. (Reproduced from Maloney, 2003) [89]

P = 0.006) and had higher b2 microglobulin levels (median 4.9 vs. 4.1 mg/L; P = 0.049). When the results of these trials were compared, TRM was 11 vs. 5%, median PFS was 25 vs. 30 months, and median OS was 35 vs. 41 months, respectively. These were not significantly different, whether using intent-to-treat or per-protocol analysis (Fig. 16-2). A study recently published by an Italian group found a different result [92]. Two hundred and forty five consecutive patients with early responding myeloma were enrolled, and 162 underwent HLA-typing. Eighty patients had an HLA-identical sibling identified and 58 completed the sequential autologous followed by nonmyeloablative allogeneic transplant (“autograft– allograft”). Of the remaining 82 patients whose HLA-typed siblings were not matched, 46 completed tandem autologous transplant (“double-autologous”). The autograft–allograft group received melphalan 200 mg/m2 as conditioning

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma 

Fig. 16-2.  Overall (left) and event-free (right) survival in the French IFM 99-03 and 99-04 trials. (Reproduced from Garban, 2006) [91]

Fig. 16.3.  Overall (left) and event-free (right) survival in the Italian trial of sequential autologousnonmyeloablative allogeneic transplantation. (Reproduced from Bruno, 2007) [92]

for the first transplant, followed by 200  cGy TBI as sole conditioning for the second [93]. GVHD prophylaxis was cyclosporine and mycophenolate mofetil. The double-autologous group received melphalan 100–200  mg/m2 for each transplant. TRM was 10% in the autograft–allograft group and 2% in the double-autologous group. By intent-to-treat analysis, the presence of an HLA-identical sibling resulted in improved PFS and OS: 35 vs. 29 months, and 80 vs. 54 months, respectively (Fig. 16-3). In a per-protocol comparison of patients who actually received the assigned treatment, PFS remained superior for the auto-allograft patients. The results of these two trials are strikingly divergent. In the IFM study, median survival of the autograft-allograft group was 35 months, whereas in the Italian study median survival was 80 months. A number of factors may have contributed to this discrepancy. The patient population in the IFM trial was restricted to high-risk patients, who were less likely to respond to any treatment; the Italian study enrolled consecutive patients. Additionally, different conditioning regimens were used in the two trials: fludarabine-based vs. the potentially less toxic 200  cGy TBI. Finally, the conditioning used for the autologous transplants was also different. In the IFM study, relatively high doses of melphalan were used (200 followed by 220  mg/m2 in the doubleautologous arm) which might have improved results of tandem autografts, whereas in the Italian study, lower doses were used (100–200  mg/m2 in the double-autologous arm), which might have worsened results when compared to the autograft–allograft arm.

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Corroborative data regarding tandem autograft–allografts for myeloma will be provided by the larger North American BMT CTN 0102 trial, in which patients were biologically assigned to receive either two melphalan 200 mg/m2 autografts or an autograft–allograft strategy using 200  cGy TBI for the nonmyeloablative conditioning. This trial closed to accrual in March 2007, and preliminary results will be available in the next few years.

6.  Donor Lymphocyte Infusion and Post-Transplant Management DLI has been shown to induce responses for both persistent and recurrent disease after both myeloablative [25, 26] and nonmyeloablative [27, 94] allogeneic transplants for myeloma. In published series of 25–63 patients receiving DLI for persistent or recurrent disease, response rates range from 38 to 52%, with CR rates from 17 to 28%. Median survival in the larger series is approximately 2 years after DLI [25, 27], suggesting that DLI may not be curative in this setting. In one series of 54 patients given DLI after myeloablative transplant, the strongest predictor of response was the presence of acute or chronic GVHD [25]. GVHD also predicted response to DLI when given to 63 patients after nonmyeloablative transplant, although there was no effect on PFS or OS [27]. Novel agents, drugs such as thalidomide, have also been used for relapsed or persistent disease after an allograft. In one study, 31 patients received thalidomide for progression following allogeneic transplant: nine achieved a response, three with very good PR [95]. Five patients also developed GVHD, including the three who achieved very good PR, suggesting that thalidomide may work in these patients by modulating the donor graft. Thalidomide in combination with DLI has also been used effectively for patients not responding to DLI alone, as has been bortezomib [96, 97]. Molecular monitoring of disease status after transplantation is also promising. PCR reactions can be designed based on an individual’s clonal heavy chain rearrangement, and persistent PCR negativity is referred to as molecular remission. Molecular remissions are rarely achieved with autologous transplants (as virtually all reinfused stem cell products contained residual myeloma cells), whereas a higher proportion of patients achieve molecular remission after allogeneic transplant [98]. In a group of 48 patients who underwent allogeneic transplant, the risk of relapse was 0% for PCR-negative patients, 33% for PCR-variable patients, and 100% for PCR-positive patients [99]. Thus, it might be possible to target patients who do not achieve a molecular remission after allogeneic transplantation; these patients might selectively benefit from additional therapies before clinical relapse occurs.

7. Conclusions Multiple myeloma is a chronic bone marrow malignancy, and allogeneic hematopoietic stem cell transplantation holds great promise of eradicating disease while inducing a graft-versus-myeloma anti-tumor effect. Until recently,

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma 

the TRM associated with therapy has limited use of this treatment modality. Toxicity has been reduced with nonmyeloablative conditioning or T-cell depleted graft processing, but these approaches can result in an increased rate of relapse. The optimal setting in which to use these nonmyeloablative transplants has yet to be determined, but disease remission prior to transplant leads to improved outcome. The strategy of sequential autologous transplantation followed by nonmyeloablative allogeneic transplantation has acceptable toxicity, and evidence from at least one randomized trial shows improved OS relative to a tandem autologous transplant strategy. Additional corroborative evidence will certainly be required, however, and will be available from the larger North American BMT CTN 0102 trial. Agents with novel mechanisms of action (bortezomib, thalidomide, and lenalidomide) are now routinely incorporated into the early therapy of myeloma. These agents have been used alone or in combination, as part of initial induction therapy or as salvage therapy for relapse, with great success but without cure. Future research will determine the best combination and sequence of these therapies. Improved approaches to autologous and allogeneic transplant hold promise for improved outcomes for patients with multiple myeloma.

References 1. Jemal A, Siegel R, Ward E et al (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66 2. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6,633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol 1998;16:3832–3842 3. Gregory WM, Richards MA, Malpas JS (1992) Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: An overview of published trials. J Clin Oncol 10:334–342 4. Facon T (2004) Randomized clinical trial comparing melphalan-prednisone (MP), MP-thalidomide (MP-THAL) and high-dose therapy using melphalan 100 MG/ M2 (MEL100) for newly diagnosed myeloma patients aged 65–75 years. Interim analysis of the IFM 99-06 trial on 350 patients. Blood 104, Abstract 206 5. Palumbo A, Bringhen S, Caravita T et al (2006) Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 367:825–831 6. Attal M, Harousseau JL, Stoppa AM et  al (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335:91–97 7. Child JA, Morgan GJ, Davies FE et al (2003) High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875–1883 8. Pasquini M (2006) Report on state of the art in blood and marrow transplantation. In: Center for international blood and marrow transplant research (CIBMTR) Newsletter 9. Lenhoff S, Hjorth M, Holmberg E et  al (2000) Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: A population-based study. Nordic Myeloma Study Group. Blood 95:7–11 10. Palumbo A, Triolo S, Argentino C et  al (1999) Dose-intensive melphalan with stem cell support (MEL100) is superior to standard treatment in elderly myeloma patients. Blood 94:1248–1253

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R.L. Olin et al. 11. Fermand JP, Ravaud P, Chevret S et al (1998) High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 92:3131–3136 12. Fermand JP, Katsahian S, Divine M et al (2005) High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: Long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 23:9227–9233 13. Blade J, Rosinol L, Sureda A et  al (2005) High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: Long-term results from a prospective randomized trial from the Spanish cooperative group PE. Blood 106:3755–3759 14. Barlogie B, Kyle RA, Anderson KC et al (2006) Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: Final results of phase III US Intergroup Trial S9321. J Clin Oncol 24:929–936 15. Attal M, Harousseau JL, Facon T et  al (2003) Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495–2502 16. Sonneveld P (2005) Intensive versus double intensive therapy in untreated multiple myeloma: Final analysis of the HOVON 24 trial. Blood 106, Abstract 2545 17. Cavo M, Tosi P, Zamagni E et al (2007) Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 25:2434–2441 18. Richardson PG, Schlossman R, Hideshima T, Anderson KC (2005) New treatments for multiple myeloma. Oncology (Williston Park) 19:1781–1792 discussion 1792, 1795–1797 19. Libura J, Hoffmann T, Passweg J et al (1999) Graft-versus-myeloma after withdrawal of immunosuppression following allogeneic peripheral stem cell transplantation. Bone Marrow Transplant 24:925–927 20. Tricot G, Vesole DH, Jagannath S et al (1996) Graft-versus-myeloma effect: Proof of principle. Blood 87:1196–1198 21. Aschan J, Lonnqvist B, Ringden O, Kumlien G, Gahrton G (1996) Graft-versusmyeloma effect. Lancet 348:346 22. Verdonck LF, Lokhorst HM, Dekker AW, Nieuwenhuis HK, Petersen EJ (1996) Graft-versus-myeloma effect in two cases. Lancet 347:800–801 23. Kroger N, Kruger W, Renges H et al (2001) Donor lymphocyte infusion enhances remission status in patients with persistent disease after allografting for multiple myeloma. Br J Haematol 112:421–423 24. Lokhorst HM, Schattenberg A, Cornelissen JJ et  al (2000) Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: Predictive factors for response and long-term outcome. J Clin Oncol 18:3031–3037 25. Lokhorst HM, Wu K, Verdonck LF et al (2004) The occurrence of graft-versushost disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood 103:4362–4364 26. Salama M, Nevill T, Marcellus D et al (2000) Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 26:1179–1184 27. van de Donk NW, Kroger N, Hegenbart U et al (2006) Prognostic factors for donor lymphocyte infusions following non-myeloablative allogeneic stem cell transplantation in multiple myeloma. Bone Marrow Transplant 37:1135–1141 28. Gahrton G, Tura S, Ljungman P et al (1991) Allogeneic bone marrow transplantation in multiple myeloma. European Group for Bone Marrow Transplantation. N Engl J Med 325:1267–1273 29. Bjorkstrand B (2001) European Group for Blood and Marrow Transplantation Registry studies in multiple myeloma. Semin Hematol 38:219–225

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma  30. Bensinger WI, Buckner CD, Anasetti C et al (1996) Allogeneic marrow transplantation for multiple myeloma: An analysis of risk factors on outcome. Blood 88: 2787–2793 31. Bensinger WI, Maloney D, Storb R (2001) Allogeneic hematopoietic cell transplantation for multiple myeloma. Semin Hematol 38:243–249 32. Reece DE, Shepherd JD, Klingemann HG et  al (1995) Treatment of myeloma using intensive therapy and allogeneic bone marrow transplantation. Bone Marrow Transplant 15:117–123 33. Couban S, Stewart AK, Loach D, Panzarella T, Meharchand J (1997) Autologous and allogeneic transplantation for multiple myeloma at a single centre. Bone Marrow Transplant 19:783–789 34. Russell NH, Miflin G, Stainer C et al (1997) Allogeneic bone marrow transplant for multiple myeloma. Blood 89:2610–2611 35. Cavo M, Bandini G, Benni M et al (1998) High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma. Bone Marrow Transplant 22:27–32 36. Majolino I, Corradini P, Scime R et al (1998) Allogeneic transplantation of unmanipulated peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant 22:449–455 37. Mehta J, Tricot G, Jagannath S et  al (1998) Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? Bone Marrow Transplant 21:887–892 38. Kulkarni S, Powles RL, Treleaven JG et al (1999) Impact of previous high-dose therapy on outcome after allografting for multiple myeloma. Bone Marrow Transplant 23:675–680 39. Russell N, Bessell E, Stainer C et al (2000) Allogeneic haemopoietic stem cell transplantation for multiple myeloma or plasma cell leukaemia using fractionated total body radiation and high-dose melphalan conditioning. Acta Oncol 39:837–841 40. Gahrton G, Svensson H, Cavo M et al (2001) Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: A comparison between transplants performed 1983–93 and 1994–98 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 113:209–216 41. Le Blanc R, Montminy-Metivier S, Belanger R et  al (2001) Allogeneic transplantation for multiple myeloma: Further evidence for a GVHD-associated graftversus-myeloma effect. Bone Marrow Transplant 28:841–848 42. Reynolds C, Ratanatharathorn V, Adams P et al (2001) Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 27:801–807 43. Alyea E, Weller E, Schlossman R et  al (2003) Outcome after autologous and allogeneic stem cell transplantation for patients with multiple myeloma: Impact of graft-versus-myeloma effect. Bone Marrow Transplant 32:1145–1151 44. Huff CA, Fuchs EJ, Noga SJ et  al (2003) Long-term follow-up of T celldepleted allogeneic bone marrow transplantation in refractory multiple myeloma: Importance of allogeneic T cells. Biol Blood Marrow Transplant 9:312–319 45. Kroger N, Einsele H, Wolff D et al. Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM). Bone Marrow Transplant 2003;31:973–9. 46. Lokhorst HM, Segeren CM, Verdonck LF et  al (2003) Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: A prospective evaluation of patients treated in the phase III study HOVON 24 MM. J Clin Oncol 21:1728–1733

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R.L. Olin et al. 47. Rabitsch W, Prinz E, Ackermann J et al (2004) Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation. Eur J Haematol 72:26–31 48. Arora M, McGlave PB, Burns LJ et al (2005) Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 35:1133–1140 49. Hunter HM, Peggs K, Powles R et al (2005) Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning-evidence for a superior outcome using melphalan combined with total body irradiation. Br J Haematol 128:496–502 50. Kennedy GA, Butler J, Morton J et al (2006) Myeloablative allogeneic stem cell transplantation for advanced stage multiple myeloma: Very long-term follow up of a single center experience. Clin Lab Haematol 28:189–197 51. Kuruvilla J, Shepherd JD, Sutherland HJ et  al (2007) Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant 13:925–931 52. Bjorkstrand BB, Ljungman P, Svensson H et al (1996) Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: A retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 88:4711–4718 53. Barlogie B (2003) Comparable survival in multiple myeloma (MM) with high dose therapy (HDT) employing MEL 140  mg/m2 + TBI 12  Gy autotransplants versus standard dose therapy with VBMCP and no benefit from interferon (IFN) maintenance: Results of Intergroup Trial S9321, Blood 102, Abstract 135 54. Bensinger WI, Demirer T, Buckner CD et al (1996) Syngeneic marrow transplantation in patients with multiple myeloma. Bone Marrow Transplant 18:527–531 55. Gahrton G, Svensson H, Bjorkstrand B et al (1999) Syngeneic transplantation in multiple myeloma – a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 24:741–745 56. Bensinger WI, Martin PJ, Storer B et al (2001) Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344:175–181 57. Ballen KK, King R, Carston M et al (2005) Outcome of unrelated transplants in patients with multiple myeloma. Bone Marrow Transplant 35:675–681 58. Alyea E, Weller E, Schlossman R et  al (2001) T-cell-depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: Induction of graft-versus-myeloma effect. Blood 98:934–939 59. Gahrton G, Tura S, Ljungman P et al (1995) Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 13:1312–1322 60. Gahrton G, Iacobelli S, Apperley J et al (2005) The impact of donor gender on outcome of allogeneic hematopoietic stem cell transplantation for multiple myeloma: Reduced relapse risk in female to male transplants. Bone Marrow Transplant 35:609–617 61. Badros A, Barlogie B, Siegel E et  al (2002) Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 20:1295–1303 62. Einsele H, Schafer HJ, Hebart H et al (2003) Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning. Br J Haematol 121:411–418 63. Garban F, Attal M, Rossi JF et  al (2001) Immunotherapy by non-myeloablative allogeneic stem cell transplantation in multiple myeloma: Results of a pilot study as salvage therapy after autologous transplantation. Leukemia 15:642–646 64. Gerull S, Goerner M, Benner A et al (2005) Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma. Bone Marrow Transplant 36:963–969

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma  65. Giralt S, Aleman A, Anagnostopoulos A et  al (2002) Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma. Bone Marrow Transplant 30:367–373 66. Kroger N, Sayer HG, Schwerdtfeger R et al (2002) Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 100:3919–3924 67. Kroger N, Perez-Simon JA, Myint H et al (2004) Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 10:698–708 68. Lee CK, Badros A, Barlogie B et al (2003) Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning. Exp Hematol 31:73–80 69. Ma SY, Lie AK, Au WY et  al (2004) Non-myeloablative allogeneic peripheral stem cell transplantation for multiple myeloma. Hong Kong Med J 10:77–83 70. Majolino I, Davoli M, Carnevalli E et  al (2007) Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma. Leuk Lymphoma 48:759–766 71. Mohty M, Boiron JM, Damaj G et al (2004) Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 34:77–84 72. Peggs KS, Mackinnon S, Williams CD et al (2003) Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: Limited efficacy of graft-versustumor activity. Biol Blood Marrow Transplant 9:257–265 73. Perez-Simon JA, Sureda A, Fernandez-Aviles F et  al (2006) Reduced-intensity conditioning allogeneic transplantation is associated with a high incidence of extramedullary relapses in multiple myeloma patients. Leukemia 20:542–545 74. Schmidt-Hieber M, Blau IW, Trenschel R et al (2007) Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma. Bone Marrow Transplant 39:389–396 75. Shimazaki C, Fujii H, Yoshida T et  al (2005) Reduced-intensity conditioning allogeneic stem cell transplantation for multiple myeloma: Results from the Japan Myeloma Study Group. Int J Hematol 81:342–348 76. van Dorp S, Meijer E, van de Donk NW et al (2007) Single-centre experience with nonmyeloablative allogeneic stem cell transplantation in patients with multiple myeloma: Prolonged remissions induced. Neth J Med 65:178–184 77. Zhang XH, Huang XJ, Liu KY et al (2007) Modified conditioning regimen busulfancyclophosphamide followed by allogeneic stem cell transplantation in patients with multiple myeloma. Chin Med J (Engl) 120:463–468 78. Perez-Simon JA, Diez-Campelo M, Martino R et al (2005) Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graftversus-host disease after allogeneic transplantation. Br J Haematol 130:394–403 79. Crawley C, Lalancette M, Szydlo R et al (2005) Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: An analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood 105: 4532–4539 80. Georges GE, Maris MB, Maloney DG et  al (2007) Nonmyeloablative unrelated donor hematopoietic cell transplantation to treat patients with poor-risk, relapsed, or refractory multiple myeloma. Biol Blood Marrow Transplant 13:423–432 81. Crawley C, Iacobelli S, Bjorkstrand B et al (2007) Reduced-intensity conditioning for myeloma: Lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 109:3588–3594

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R.L. Olin et al. 82. Perez-Simon JA, Martino R, Alegre A et  al (2003) Chronic but not acute graft-versus-host disease improves outcome in multiple myeloma patients after non-myeloablative allogeneic transplantation. Br J Haematol 121:104–108 83. Kroger N, Schilling G, Einsele H et al (2004) Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation. Blood 103:4056–4061 84. Qazilbash MH, Saliba R, De Lima M et al (2006) Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma. Cancer 106:1084–1089 85. Lee CK, Zangari M, Fassas A et al (2006) Clonal cytogenetic changes and myeloma relapse after reduced intensity conditioning allogeneic transplantation. Bone Marrow Transplant 37:511–515 86. Carella AM, Beltrami G, Corsetti MT et al (2004) A reduced intensity conditioning regimen for allografting following autografting is feasible and has strong antimyeloma activity. Haematologica 89:1534–1536 87. Galimberti S, Benedetti E, Morabito F et  al (2005) Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res 29:961–966 88. Kroger N, Schwerdtfeger R, Kiehl M et al (2002) Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 100:755–760 89. Maloney DG, Molina AJ, Sahebi F et al (2003) Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102:3447–3454 90. Seok L (2003) Autologous stem cell transplantation followed by nonmyeloablative allogeneic stem cell transplantation as a first-line therapy in patients with newly diagnosed multiple myeloma: A prospective phase 2 study. Blood 102, Abstract 91. Garban F, Attal M, Michallet M et al (2006) Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 107:3474–3480 92. Bruno B, Rotta M, Patriarca F et  al (2007) A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 356:1110–1120 93. McSweeney PA, Niederwieser D, Shizuru JA et al (2001) Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97:3390–3400 94. Ayuk F, Shimoni A, Nagler A et  al (2004) Efficacy and toxicity of low-dose escalating donor lymphocyte infusion given after reduced intensity conditioning allograft for multiple myeloma. Leukemia 18:659–662 95. Mohty M, Attal M, Marit G et al (2005) Thalidomide salvage therapy following allogeneic stem cell transplantation for multiple myeloma: A retrospective study from the Intergroupe Francophone du Myelome (IFM) and the Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC). Bone Marrow Transplant 35:165–169 96. Kroger N, Shimoni A, Zagrivnaja M et al (2004) Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma. Blood 104:3361–3363 97. van de Donk NW, Kroger N, Hegenbart U et  al (2006) Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation in multiple myeloma. Blood 107:3415–3416

Chapter 16  Allogeneic Transplantation for the Treatment of Multiple Myeloma  98. Corradini P, Voena C, Tarella C et al (1999) Molecular and clinical remissions in multiple myeloma: Role of autologous and allogeneic transplantation of hematopoietic cells. J Clin Oncol 17:208–215 99. Corradini P, Cavo M, Lokhorst H et al (2003) Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood 102:1927–1929

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Chapter 17 Blood Vs. Marrow Allogeneic Stem Cell Transplantation Brian McClune and Daniel Weisdorf

1. Introduction Since first being reported in 1989 [1], peripheral blood stem and progenitor cells (PBPC) have become extensively used as a graft source in allogeneic transplantation. Case series demonstrating its feasibility in the allogeneic setting first appeared in the mid-1990s [2–4]. In 2007, data from the Center for International Blood Marrow Transplant Research (CIBMTR) indicated that nearly 80% of all allogeneic transplants performed between 2002 and 2006 used PBPC for those aged >20 years versus 1997–2001 when marrow grafts were used in nearly 60% of all adult transplants [5]. Contributing to this broadening use of peripheral blood stem cell transplants is the increased utilization of unrelated donors (URD) [6], more experience with the procedure, and the suggestion of superior outcomes in certain diseases and settings. Despite the rapid acceptance of PBPC for transplantation, only recently have data from randomized trials [7–20], large registry-based data [21, 22], and studies with some long term follow-up become available. This chapter will review the known biological and clinical characteristics of PBPC transplantation, with an emphasis on information obtained from randomized trials and large registry analyses.

2. Biology of Peripheral Blood Progenitor and Stem Cells Normally, very low numbers of hematopoietic progenitor cells circulate in the peripheral blood (0.06% of all nucleated cells) [23]. They are generally identified by surface marker expression of CD34 (stem cell antigen), though their progeny will also express CD34 in addition to lineage specific markers after commitment to myeloid, lymphoid, or erythroid lineages. However, within the CD34+ lineage-negative population are the hematopoietic stem cells capable of sustaining long-term engraftment. In recent years, other surrogates to identify and efnumerate hematopoietic stem and progenitors cells (HSC) have also been

From: Allogeneic Stem Cell Transplantation, Contemporary Hematology, Edited by: H.M. Lazarus and M.J. Laughlin, DOI 10.1007/978-1-59745-478-0_17, © Springer Science + Business Media, LLC 2003, 2010

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identified. CD133 is a pentaspan molecule found on cells more primitive than CD34+ cells and is down-regulated early in differentiation [25]. The marker is also found on primitive endothelial and neuronal cells and thought to be involved in plasma membrane organization and structure. It was recognized that CD133 expression was restricted to CD34+ bright cells and that long-term hematopoietic reconstitution could be demonstrated not only in animals but also in humans with cells that were CD133+ [26]. Isidori et al. published their data on CD133+ selected grafts in 12 patients with chronic lymphocytic leukemia (CLL) undergoing autologous transplantation [26]. All patients exhibited rapid engraftment and platelet recovery that was independent of the number of CD133+ cells infused. Hicks et  al. described 20 myeloma patients after autologous transplantation and evaluated numbers of viable CD34+ and CD34+CD133+ cells infused along with engraftment kinetics [28]. Viable CD34+CD133+ cells correlated well with neutrophil recovery with more rapid engraftment accompanying higher CD34+ or CD34+CD133+ cell doses. No correlation with platelet engraftment was apparent suggesting that CD133+ determination may best be used in predicting neutrophil recovery. Two publications including a total of only 15 patients, report on the feasibility of CD133+ selection in the allogeneic setting and suggest that the repopulating potential of CD133+ selected cells is at least as good as CD34+ selection and provides less acute toxicities to patients from graft-versus-host disease (GVHD) likely because of a significant decrease in T cells with the allograft [26, 29]. Whether this is enough to supplant CD34+ selection will only be borne out by future studies. Administration of cytokines is generally needed to increase the numbers of HSC in circulation. This results not only in an increase in the total leukocyte count but also in a preferential increase in the concentrations of PBPC [24, 30]. Currently, only granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) are FDA approved for mobilization of stem cells with G-CSF being the most widely used. Earlier studies showed that GM-CSF is as effective as G-CSF in terms of CD34+ yield but may have an unfavorable side effect profile. These adverse effects may be balanced by the reduced occurrence of acute GVHD in the GM-CSF mobilized group although this has not been confirmed nor widely applied [30–33]. The mechanism of cytokine-mobilization is not well understood despite extensive study over the last 10  years. Adhesion molecules binding HSC to the marrow microenvironment and their interaction with these cytokines play a significant role in this process. Of particular importance is the CXC family which includes stromal-derived factor-1 (SDF-1). This factor interacts with CXCR4 to help regulate migration of CD34+ cells from the marrow space and has been recently exploited to further increase yields in stem cell mobilization (see below). The N-terminal portion of the cytokine GROb, multiple proteases that help break down adhesions in the marrow niche and even neuron-regulatory signals likely participate in movement of CD34+ cells into the circulation [35–37]. Other agents can mobilize stem cell populations including pegylated filgrastim (Neulasta), FLT-3 ligand in combination with G-CSF [38, 39], and a newer agent called AMD3100 (plerixafor). AMD3100 is a bicyclam derivative first identified as an agent with anti-HIV activity in the 1980s that induced sustained

Chapter 17  Blood Vs. Marrow Allogeneic Stem Cell Transplantation 

neutrophilia [40]. Its mechanism of action was eventually deduced to be reversible competitive inhibition of SDF-1 binding to the CXCR4 receptor, favoring mobilization of CD34+ cells into the circulation. Preclinical and animals trials demonstrated that AMD3100 could mobilize progenitor cells for engraftment. Investigations showed up to tenfold increases in PBPC following a single dose of 240 mcg/kg. Commonly reported side effects included erythema and pain at the injection site, nausea, perioral numbness, and headache [41]. Further study of the drug in the autologous transplant setting for myeloma, and nonHodgkins and Hodgkins lymphoma show that when added to G-CSF, collections have more CD34+ cells per leukopheresis, patients require fewer total collections, and that stable engraftment is successfully achieved in nearly all patients [42–44]. Subsequently, Devine et al. performed a pilot study examining the safety and efficacy of plerixafor in mobilization of HLA-matched related donors (MRD) [45]. The study evaluated mobilization with either one or two doses of AMD3100 at 240 mcg/kg and then after a 1 week washout period, mobilization with G-CSF alone. Eight of nine donors enrolled yielded at least 2.0 × 106 CD34+ cells/kg recipient weight after one or two collections. The grafts contained fewer CD34+ cells and greater numbers of T-,B-, and NK-cells compared to the G-CSF mobilized products. Seven of the patients then proceeded to transplant using the AMD3100 mobilized cells. Engraftment was comparable to G-CSF allografts as was the incidence of acute GVHD. Further trials to assess this new agent alone or in combination may be promising in limiting donor morbidity as long as recipient outcomes are carefully assessed as well.

3.  Clinical Aspects of Peripheral Blood Stem Cell Transplantation Knowledge of the clinical aspects of PBPC transplantation has increased dramatically in recent years with the proliferation of studies comparing it to marrow transplantation. While early results are clear, late outcomes continue to require further investigation and longer patient follow-up. 3.1. Graft Characteristics The evidence that greater CD34+ cell numbers are obtained using peripheral blood harvesting is strong. Seven of ten randomized trials published to date have harvested and infused greater numbers of CD34+ cells from peripheral blood donors than from marrow donors [7, 13–14, 16–19]. Three of these studies demonstrated a statistically significant increment in blood progenitors, with at least twice the number collected by apheresis as were collected from marrow [13, 14, 17]. Graft composition data were not uniformly available in a comparison of peripheral blood vs. marrow stem cell transplantation reported from the International Bone Marrow Transplant Registry (IBMTR) [21], but several smaller series comparing PBPC recipients with historical or nonrandomized controls have shown higher CD34+ cell concentrations in peripheral blood [23, 24]. The minimum number of cells needed for successful engraftment remains unclear. It has been estimated that approximately 2.5–5 × 106 CD34+ cells/kg is sufficient for consistently rapid engraftment [3], but no experimental

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evidence confirms this hypothesis. A higher CD34+ cell dose has been reported to facilitate more rapid platelet engraftment in allogeneic transplants [46], as was also shown in autologous transplants [47]. Data from clinical trials of PBPCs suggest that higher CD34+ counts promote more rapid neutrophil and platelet engraftment in the allogeneic setting as well, but other cell populations also affect both the quality of the graft and the likely occurrence of GVHD. 3.2. Engraftment Both neutrophil and platelet engraftment consistently occur more rapidly when using peripheral blood grafts as opposed to marrow grafts. All ten published randomized trials found a shorter time to both neutrophil and platelet engraftment (Table  17.1), as do virtually all smaller series with nonrandomized controls. In the ten published randomized trials, neutrophil engraftment occurred 1–6 days earlier in PBPC transplants than in marrow transplants. Differences were statistically significant in eight of the ten trials. In the larger IBMTR analysis, neutrophil engraftment occurred 5 days earlier in PBPC transplants than in marrow transplants [21]. Platelet engraftment also occurs more rapidly using peripheral blood allografts. All randomized trials found more rapid platelet recovery, with the median differences ranging from 4 to 13  days. The IBMTR analysis found that platelet engraftment occurred a median of 7  days earlier in the PBPC transplants than in traditional marrow transplants [21]. As with neutrophil engraftment, numerous smaller series have shown similar results. Seven of the ten randomized trials reported information about transfusions administered during the observational period. In the largest trial, the median days of platelet transfusions required in peripheral blood recipients was significantly less than that in marrow recipients (8 vs. 10 days; p = 0.0029); red blood cell (RBC) transfusion requirements were not reported [8]. One of the larger European trials found similar results in terms of platelet transfusions with the time to last platelet transfusion being less in the PBPC transplant arm (21 vs. 26 days, p = 0.03). Time to last red blood cell transfusion was also less (42 vs. 68 days, p < 0.005) [19]. There was no difference in the number of RBC transfusions between the marrow and blood groups in the Canadian trial [18]. A smaller trial found that fewer platelet transfusions were required in peripheral blood recipients (PBPC 12.5, BMT 17.5) but similar RBC transfusions in the two groups (PBPC 5, BMT 6) [7]. 3.3. Graft Versus Host Disease Since the earliest reports of peripheral blood allografting, there has been considerable concern that because such high numbers of lymphocytes are transplanted in peripheral blood grafts, GVHD would occur at high rates [1–4]. In clinical studies to date, however, little data has emerged suggesting differences in overall rates of acute GVHD [10, 13, 14, 17, 18, 20]. In contrast, chronic GVHD has been shown to occur more commonly in patients receiving peripheral blood allografts [21, 48]. Because of the longer observation time needed to ascertain the incidence of chronic GVHD, data are incomplete in many studies.

1998

1998

1999

2000

2000

2000

2001

2002

2003

2005

EBMT [7–9]

Brazil [10, 11]

Mahmoud [12]

France [13]

U.K. [14]

Hedal [15, 16]

U.S [17].

Canada [18]

Dutch [19]

Oehler [20]

32

56

109

81

31

20

48

15

18

163

PBSC

N

40

54

118

91

30

19

52

15

19

166

BMT

b

Indicates p < 0.05 for given result Reported as proportions, not estimation NR not reported

a

Year

Trial

CSA/Pred

CSA/MTX

GVHD prophylaxis

CSA/MTX

CSA/MTX

CML

AML,MDS, MM, lymphoma,

CML, AML, MDS

AML, ALL, NHL, HD, CML, MM, MDS,

CML, AML, ALL, MM

CSA/MTX

CSA

CSA/MTX

CSA/MTX

CSA/MTX

ALL, AML, CML, NHL, CSA/MTX MDS, MM

ALL, AML in first or second CRCML in first CP

AML, ALL, MDS, SAA

CML, AML, ALL, MDS, CSA/MTX NHL, MMEarly and advanced disease

AML, ALL in first or second remission, CML in first chronic phase

Major diagnoses

16 days

15 days

19 days

16 days

17 days

17 days

15 days

NR

17 daysa

20 daysa

BMT

15 days

11 days 13 days

13 days

16 days 25 days 14 days

21 daysa

23 daysa 23 daysa

21 daysa

23 daysa 20 daysa 21 daysa

21 days

38 days

22 daysa

19 daysa

21 daysa

18 daysa

26 daysa

Exact numbers NRa

12 days

15 days

15 daysa

18 days

PBSC

Platelet recovery

BMT

Exact numbers

16 days

12 days

PBSC

Neutrophil engraftment

Table 17-1.  Randomized clinical trials investigating PBPC vs. BMT.

82%

48%

68%

(p = 0.06)

66%

63%

70%

67%

NR

51%

58%

PBSC

84%

57%

60%a

54%

83%b

63%

65%

47%

65%

BMT

Overall survival

55

52

44

64

21

50

44

6.7

27

52

49

37

44

57

10

47

37%

40%

28%a

53%

55%a

BMT

59%

50%

85%

46%

50%

42%

69%

35%

(p = 0.03 for extensive cGVHD)

57%

44%

50%

NR

47a

42

71%

73%

PBSC

Chronic GVHD

19

39a

PBSC BMT (%) (%)

Acute GVHD (grade II–IV)

36 months

37 months

33 months

26 months

5 years

33 months

20 months

NR

>5 years

3 years

Median follow-up

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3.3.1. Acute Graft Versus Host Disease Overall rates of acute GVHD are generally similar in patients receiving peripheral blood or marrow transplants. Seven of ten randomized trials have found a 44–68% rate of grade II–IV acute GVHD in patients receiving peripheral blood transplants compared with a 37–57% rate in patients receiving marrow transplants [7, 13, 14, 17–20]. IBMTR analyses (Fig. 17.1) found that grade II–IV acute GVHD occurred in 40% of patients receiving peripheral blood transplants and 35% of patients receiving marrow transplants [21]. Only one study reported a significantly greater rate of acute GVHD using PBPC (47% vs. 7%, p = 0.013) [12]. One randomized trial, published only in abstract form, found similar rates of grade II–IV acute GVHD in peripheral blood and marrow transplant recipients (PBPC 54% vs. BMT 48%), but PBPC patients were more likely to develop steroid-dependent or refractory GVHD (PBPC 50% vs. BMT 14%, p = 0.003) [82]. In this trial, grade III–IV acute GVHD was also higher in patients receiving peripheral blood transplants (PBPC 46% vs. BMT 17%, p = 0.02). Rates of grade III–IV acute GVHD were found to be significantly worse with PBPC in the largest randomized trial (PBPC 28% vs. BMT 16%; p = 0.0088) [8]. 3.3.2. Chronic Graft Versus Host Disease A growing body of evidence suggests that chronic GVHD is more frequent in patients receiving peripheral blood allografts. Reported results from all randomized trials published show an increased risk of chronic GVHD [8–20], even though follow-up periods in these trials are generally short and may not

Fig. 17-1.  Probabilities of grades II–IV acute graft versus host disease (GVHD) after HLA-identical sibling blood stem cell transplantation compared with bone marrow transplantation for acute leukemia and CML. Probabilities were derived from multivariate Cox proportional hazards models and adjusted for effects of other significant covariates. Adapted from Champlin et al. Blood 2000

Chapter 17  Blood Vs. Marrow Allogeneic Stem Cell Transplantation 

fully represent the burden of disease in study participants. One trial designed to determine differences in GVHD on the basis of stem cell source closed enrollment early because the incidence of extensive chronic GVHD was significantly greater in patients receiving peripheral blood (77% vs. 27%) [80]. The IBMTR analysis (Fig. 17.2) also found significantly more chronic GVHD in PBPC transplants (65% vs. 53%, p = 0.05) [21], but the difference between groups did not become evident until 10–12 months after transplant. Moreover, rates of chronic GVHD did not plateau until 12–15  months after treatment, suggesting that follow-up times less than 2 years are inadequate for determining true incidence of chronic GVHD. The difference between the PBPC and BMT groups worsened in an updated analysis (PBPC 61% vs. BMT 45%; RR 1.65, p < 0.001) [22]. Another smaller cohort initially reported no difference in chronic GVHD at a median follow-up of less than 1  year [49], but more chronic GVHD was noted in peripheral blood recipients when follow-up was extended to 2 years [50]. Risk factors for developing chronic GVHD in the IBMTR analysis included gender, no GVHD prophylaxis, and age ³40 [22]. Two trials that reported an increased risk of chronic GVHD used limited methotrexate prophylactic regimens [10, 13] suggesting that prophylaxis with four doses of methotrexate is important. A meta-analysis done by the Stem Cell Trialists’ Collaborative Group confirmed a significant increase in the odds of developing chronic GVHD in patients undergoing PBPC transplantation (OR 1.43, p < 0.016); however, it did not confirm a statistical benefit from the day 11 dose of methotrexate [51]. In one report, chronic GVHD after PBPC transplant required treatment with more regimens and for longer periods suggesting that chronic GVHD related to PBPC is more difficult to control [52]. Follow up reports from other studies are awaited in order to better assess any differences in rates and severity of chronic GVHD.

Fig. 17-2.  Probabilities of chronic GVHD (limited or extensive disease) after HLAidentical sibling blood stem cell transplantation compared with bone marrow transplantation for acute leukemia and CML. Probabilities were derived from multivariate Cox proportional hazards models and adjusted for effects of other significant covariates. Champlin et al., Blood 2000. Used with permission

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3.4. Infections Some, though unconfirmed, data suggest that PBPC recipients have fewer infectious complications than marrow recipients. The Seattle report showed that culture-proven infections were 1.7 times more frequent in marrow recipients compared to PBPC recipients between days 30 and 365 of transplant (p = 0.001) [53]. The rate of infections requiring inpatient treatment was 2.4 times higher in marrow recipients (p = 0.002). The difference in infection rates was greatest for fungal infections, but was also apparent for bacterial and viral infections. Deaths from infections were slightly more frequent after BMT. Nucci reviewed infection rates as part of a larger randomized trial [54]. No differences in the frequency of fever, infection, use of antifungal therapy, or length of antibiotic pre-engraftment use were found. However, following engraftment, more extensive chronic GHVD in the PBPC group led to more immunosuppressant and antimicrobial use as well as more frequent infections although there was no increased need for hospitalization or survival difference (40% BMT group, 61% PBPC group, p = 0.27). In a multivariate model, only the duration of steroid use was associated with more infections (p < 0.001). Additional analyses including larger number of patients and carefully organized, prospective, clinical trials are required to probe infection morbidity more fully. 3.5. Survival Despite the popular shift to PBPC grafting, the available data do not demonstrate a clear survival benefit using PBPC. The largest EBMT uiuiu randomized trial demonstrated no overall survival difference between PBPC transplantation and BMT (58% vs. 65%, HR of death for PBPC 1.26, p = 0.19) [9]. Another trial showed a trend to modestly worse overall survival with PBPC [15]. The largest US, randomized trial published to date found a marginal benefit in 2 year survival rate (66% vs. 54%) with PBPC (p = 0.06) although longer follow-up has not confirmed this advantage [17]. A metaanalysis of individual patient data from nine randomized controlled trials also failed to show a survival benefit of PBPC transplantation (Fig. 17.3) [55]. Some studies reported a survival advantage in patients with advanced stage disease. However, updated IBMTR 6 year follow-up data showed lower transplant related mortality (TRM) with PBPC in advanced acute leukemias but equivalent survival rates for both early and advanced disease [22]. It is hypothesized that a more vigorous allogeneic response following PBPC transplantation and thus more potent GVL may reduce relapse rates. No consistent differences in causes of death have been reported. 3.6. Quality of Life Only a few studies have analyzed quality of life in survivors of peripheral blood transplants. Generally, data come from series comparing recent peripheral blood transplant recipients with historical controls who received marrow, limiting the validity of measures that may vary depending on length of follow-up. In one comparison with historical marrow controls 48% of surviving peripheral blood recipients had Karnofsky scores of £80 vs. only 5% of marrow

Chapter 17  Blood Vs. Marrow Allogeneic Stem Cell Transplantation  100

289

PBSCT

90

BMT__

80 Survival (%)

70

56.85%

60 50

55.76%

40

56.85%

53.15%

30 20 10 0

Chi2 Statistic: 1.84 P = 0.17495 Abs Diff at 5 yrs = 2.54%

0

1

2

3 Years

4

5

6

Death/Person-years: PBSCT : 142/455.10 42/351.86 13/292.90 5/174.03 5/99.11 0/45.85 BMT__ : 168/453.36 45/338.56 11/278.98 3/143.07 2/77.44 2/39.45

Fig. 17-3.  Overall survival of 1,111 patients undergoing peripheral blood stem cell (PBSCT) vs. marrow (BMT) transplantation; Abs diff, Absolute difference. (Reproduced and adapted with permission from Stem Cell Trialists’ Collaborative Group: Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005; 23(22):5084. © 2008 American Society of Clinical Oncology. All rights reserved

recipients [48]. Another uncontrolled series found that 64% of blood allograft survivors had Karnofsky scores between 70 and 80 [56]. Chronic GVHD is responsible for most of the excess morbidity accompanying allotransplants. No data on quality of life was included in other published trials. 3.7. Unrelated Peripheral Blood Transplants No randomized trials are reported comparing URD marrow versus peripheral blood allografting. Previous studies with adequate follow-up suggested that there was virtually no difference in rates of acute or chronic GVHD or overall survival in utilizing mobilized PBPC or marrow from URD (median follow-up 4.4, 5 years respectively) [57]. However, extensive chronic GVHD was significantly more common in the PBPC group. OS for both groups was 42%. The CIBMTR reported on URD transplants (2000–2003) including 331 PBPC and 586 BMTs for leukemia/MDS with a median 3  year follow-up [58]. Rates of grade II–IV acute GVHD and chronic GVHD were significantly higher with PBPC transplants (58% vs. 45%, p < 0.001; 56% vs. 42%, p < 0.001); TRM and relapse were similar as was leukemia free survival (30% PBPC vs. 32% BM). A continuing, prospective trial sponsored by the NHLBI/ NCI-funded Blood and Marrow Clinical Trials Network (BMT CTN), 0201, is testing BM versus filgrastim-primed PBPC from unrelated donors. This large trial (n = 550) will complete accrual in early 2009 and is critical to further inform graft choices for URD allografts.

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3.8. Cytokine-Primed Marrow Transplantation Some early data describes G-CSF primed marrow as an alternative source of stem cells. The rationale for marrow priming is on the basis of murine [59] and human [61, 62] studies demonstrating improved repopulating ability of G-CSF primed bone marrow, similar engraftment rates to PBPC transplant, and less acute and chronic GVHD [62, 63]. Cytokine primed marrow grafts generally include higher number of CD34+ cells than unprimed marrow and up to 1 log fewer T cells than PBPC allografts [64, 65]. Lowenthal et al. recently showed that 4 days vs. 6 days of G-CSF prior to marrow harvest allowed for the greatest yield of CD34+ cells/kg [64]. Several single-institution studies highlight the use and safety of primed marrow transplantation [65,57]. One report compared G-CSF mobilized marrow to mobilized PBPC autologous transplant for lymphoma. No significant differences were noted in neutrophil recovery, blood product support, febrile days, or antibiotic days. The PBPC led to slightly greater time to 50 × 109/L platelets (16 days BM vs. 14 days PBPC, p = 0.011). [67] Weisdorf et  al. studied autologous mobilized marrow and PBPC in NHL and Hodgkins patients randomly assigned to either GM-CSF or G-CSF. Graft composition analysis showed more long-term culture-initiating cells (LTC-IC) and committed precursors (CFU-GM) mobilized by either cytokine over unstimulated controls. G-CSF autografts contained more CFU-GM and LTC-IC than GM-CSF mobilized grafts. RBC and platelet but not neutrophil recovery was quicker in marrow mobilized with GM-CSF or PBPC mobilized with G-CSF (p = 0.01) resulting in faster hospital discharge. Similar relapsefree survival suggested that cytokine-primed marrow was as effective as PBPC for autologous transplantation [68, 69]. Morton et  al. randomized 57 patients to receive an allogeneic graft using G-CSF mobilized PBPC or marrow stratified according to risk of relapse [62]. Donors in the marrow arm received G-CSF (10 mcg/kg/day for 5 days) followed by marrow harvest or PBPC harvest. CD34 and CD3 doses were significantly lower in marrow versus PBPC. However, there were no significant differences in neutrophil or platelet engraftment or acute GVHD. Primed marrow led to significantly less chronic GVHD than the PBPC (47% vs. 90%, p < 0.02). Steroid-refractory GVHD was more common in the PBPC arm (47% vs. 18%; p < 0.02) as well. Stem cell source did not affect 18 month survival (67% marrow vs. 64% PBPC). Another series, comparing 26 primed bone marrow recipients to a historical cohort of 20 PBPC blood transplant recipients, found similar neutrophil recovery but slightly more rapid platelet recovery with PBPC. Marrow led to less chronic GVHD (PBPC 68%, primed BMT 37% p = 0.049) but 2 year survival was similar (PBPC 60%, primed BMT 54%, p = 0.9). Other small series [71–73] and a recent review [63] show similar findings, suggesting that further study of primed marrow is warranted.

4. Donor Considerations The safety for PBPC donors has not been well studied. Although short term effects of G-CSF in normal donors are mild [75], little is known about long term effects of G-CSF. Doses of G-CSF used in peripheral blood stem cell harvests range from 2 to 24 mg/kg/d, usually 10 to16 mg/kg/d [7, 10, 12–15, 17, 20, 75].

Chapter 17  Blood Vs. Marrow Allogeneic Stem Cell Transplantation 

The most common short-term adverse effects of G-CSF administration include bone pain, headache, fatigue, fever, and nausea [76]. Less commonly, non-cardiac chest pain, insomnia, night sweats, fluid retention, and dizziness have been reported [75]. Severe side effects requiring discontinuation of G-CSF are uncommon, occurring in 1–3% of donors [76]. Laboratory abnormalities, including transient elevations of alkaline phosphatase and lactate dehydrogenase and less commonly, electrolyte disturbances, have also been noted. Both thrombocytopenia and granulocytopenia have been reported after donation, but these findings result from the leukapheresis procedure itself, not from administration of G-CSF [76]. In general, adverse effects appear to be dose related. Bony pain occurs in 50–84% of donors. It is adequately treated with overthe-counter analgesics and generally subsides within a few days. Autoimmune conditions might be exacerbated by G-CSF administration, including thyroid dysfunction [78–80]. Severe adverse reactions are rare and include 11 cases of splenic rupture; four in healthy donors. Transient increases in spleen size in up to 10% of donors had previously been noted. Additionally, transient gas exchange abnormalities have been seen in healthy donors with one case report of acute lung injury seen by day 4 of G-CSF administration [81]. Rare reports describe acute myeloid leukemia and myelodysplasia arising after G-CSF administration; [76] three in healthy sibling donors, 14 months to 5 years after G-CSF use. Laboratory data from some small studies have shown transient gene expression changes, aneuploidy, and replication asynchrony in lymphocytic cell lines. These inferential data associating G-CSF with these later marrow disorders are weak as all three patients had siblings with malignant hematopoietic conditions. The NMDP/CIBMTR is conducting a prospective study to evaluate donor safety with regard to the possible leukemogenic potential of G-CSF.

5. Cost Only one randomized trial has included an economic analysis of peripheral blood transplants compared with marrow transplants [13]. It found that overall costs of peripheral blood transplants during the first 180 days were 16% less than costs of marrow transplants. The difference was primarily a result of lower room costs in the peripheral blood group, although cost was also reduced because of fewer platelet transfusions, low laboratory fees, and lower overall drug expenses. Graft collection costs were higher in peripheral blood donors. A retrospective analysis from the Netherlands looked at the costs of either a MRD marrow transplant (MRD BMT), a MUD marrow transplant (MUD BMT) or a MRD PBPC transplant performed from 1994–1999 across four transplant centers [84]. Average cost estimates included donor identification expenses and 2  years of follow-up for those who did and did not undergo transplantation. In this analysis, PBPC transplantation was equivalent to MRD BMT (€98,977 vs. €98,334) despite the documented advantage of shorter length of hospital stays, faster hematopoietic recovery, and less antibiotic administration. MUD BMT was particularly costly (€151,754) with nearly one-third of the cost of MUD BMT attributable to transplant donor searching. With the expansion of transplant techniques to include older patients and more indications for transplant being recognized, continued scrutiny of stem cell therapies and their inherent costs is required.

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6. Conclusion Our understanding of peripheral blood stem cell allogeneic transplantation has increased markedly during the past several years. Benefits of peripheral blood transplantation may include more rapid engraftment. More data are needed about long-term survival, late effects, and the use of peripheral blood grafts from both related and unrelated donors. While marrow is no longer the standard of care for most adult transplant allografts, the risks of chronic GVHD and its accompanying morbidity and mortality could shift that paradigm back in favor of BMT. This can only be confirmed by well-designed, long-term studies and follow-up.

References 1. Kessinger A, Smith DM, Strandjord SE, Landmark JD, Dooley DC, Law P et al (1989) Allogeneic transplantation of blood-derived, T cell-depleted hemopoietic stem cells after myeloablative treatment in a patient with acute lymphoblastic leukemia. Bone Marrow Transplant 4:643–646 2. Korbling M, Przepiorka D, Huh YO, Engel H, van Besien K, Giralt S et al (1995) Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts. Blood 85:1659–1665 3. Bensinger WI, Weaver CH, Appelbaum FR, Rowley S, Demirer T, Sanders J et al (1995) Transplantation of allogeneic peripheral blood stem cells mobilized by re-combinant human granulocyte colony-stimulating factor. Blood 85:1655–1658 4. Schmitz N, Dreger P, Suttorp M, Rohwedder EB, Haferlach T, Loffler H et al (1995) Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood 85:1666–1672 5. National Marrow Donor Program (2008) Outcomes and trends. http://www.marrow. org/PHYSICIAN/Outcomes_Data/index.html. Accessed Jan 2008 6. Ringden O, Remberger M, Runde V, Bornhauser M, Blau IW, Basara N et al (1999) Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation. Blood 94:455–464 7. Schmitz N, Bacigalupo A, Hasenclever D, Nagler A, Gluckman E, Clark P et al (1998) Allogeneic bone marrow transplantation vs. filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 21:995–1003 8. Schmitz N, Beksac M, Hasenclever D et  al (2002) Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard risk leukemia. Blood 100:761–767 9. Schmitz N, Beksac M, Bacigalupo A et al (2005) Filgrastim-mobilized peripheral blood progenitor cells versus bone marrow transplantation for treating leukemia: 3-year results from the EBMT randomized trial. Hematologica 90(5):643–648 10. Vigorito AC, Azevedo WM, Marques JF, Azevedo AM, Eid KA, Aranha FJ et al (1998) A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplant 22:1145–1151 11. Vigorito AC, Comenalli Marques JF, Penteado Aranha FJ et  al (2001) A randomized prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of hematologic malignancies: an update. Haematologica 86:665–666 12. Mahmoud H, F