Amsacrine-Associated Cardiotoxicity

Amsacrine-Associated Cardiotoxicity: An Analysis of 82 Cases By Raymond B. Weiss, Antonio J. Grillo-L6pez, Silvia Marsoni, Juan G. Posada, Jr, Frank Hess, and Beverly J. Ross Amsacrine is an antileukemia drug being widely used in North America, Europe, Australia, and New Zealand. In the initial clinical trials, patients treated with amsacrine developed occasional instances of acute cardiac arrhythmias and cardiomyopathy. We review and analyze the features of cardiac abnormalities associated with amsacrine in 82 patients, 27 of whom have not been previously reported. The rest have been reported in the literature, but we have included a large amount of additional information about these patients in our analysis. We conclude that amsacrinerelated cardiac events are less common than those

IN

STUDYING the structure-antitumor relationships of bisquaternary salts, Cain et al, in New Zealand, synthesized a large number of new acridine derivatives that demonstrated antitumor activity in animal screening systems.1, 2 One of these analogs was 4'-(9-acridinylamino) methanesulfon-m-anisidide, which has now been given the generic name amsacrine. Since clinical trials began in 1977, amsacrine has been tested in many phase II and III trials and has shown significant antitumor activity in acute leukemia. In 1981, the National Cancer Institute (NCI) began providing the drug for individual patient use under the so-called Group C guidelines. Amsacrine has been marketed by Warner Lambert/Parke Davis (WL/PD) in Australia, New Zealand, CanFrom the Section of Medical Oncology, Walter Reed Army Medical Center, Washington, DC; Uniformed Services University of the Health Sciences, Bethesda, Md; Warner-Lamberti Parke-Davis,PharmaceuticalResearch, Ann Arbor, Mich; Department of Medicine, University of Michigan Medical School, Ann Arbor; and the InvestigationalDrugBranch, CancerTherapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Md. Submitted Aug 13, 1985; accepted Jan 13, 1986. The opinions expressed in this article are solely those of the authors and do not necessarily reflect those of any government agency. Address reprint requests to Raymond B. Weiss, MD, Section of Medical Oncology, Walter Reed Army Medical Center, Washington, DC 20307-5001. This is a US government work. There are no restrictionson its use. 0732-183X/86/0406-0018$0.00/0

918

related to anthracycline chemotherapeutic agents. Manifestations of such toxicity include ECG abnormalities, ventricular and atrial arrhythmias, sudden death, and congestive heart failure. There is little or no cumulative dose effect. Hypokalemia may be a risk factor for development of serious tachyarrhythmias, but such problems can occur despite a normal serum potassium level. Amsacrine appears to affect depolarization and repolarization of the heart, but the mechanism is unknown. J Clin Oncol 4:918-928 (1986). This is a US government work. There are no restrictions on its use.

ada, and a number of European countries, and new drug applications for marketing approval have been submitted to the US Food and Drug Administration. The mode of action of amsacrine is somewhat similar to that of the anthracyclines in that it acts, at least partially, by intercalation between base pairs in double-stranded DNA molecules.' The anthracyclines are known to produce both acute and chronic cardiotoxicity. The acute form is manifested by transient ECG changes and arrhythmias that may occur rarely or in as many as 41% of patients and usually appear in the first few hours or days after drug infusion. 4 These changes are usually not clinically significant and are not contraindications to continued use of the anthracyclines. The delayed form is a dose-related cardiomyopathy that can lead to congestive heart failure. The reported incidence of cardiomyopathy ranges from 0.4% to 9% with an associated lethality as high as 61%.4 Amsacrine could also have cardiotoxic effects, because it has intercalating activity that is similar to the anthracyclines. Early in the clinical trials, amsacrine was occasionally associated with cardiac toxicity.-7 Both acute (arrhythmia) and chronic (cardiomyopathy) forms of cardiac abnormalities have been reported in patients treated with this drug. 5-39

The NCI and WL/PD continually monitor toxicity of drugs for which they have filed the notice of investigative new drug with the FDA. Investi-

Journal of Clinical Oncology, Vol 4, No 6 (June), 1986: pp 918-928

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

919

AMSACRINE-ASSOCIATED CARDIOTOXICITY

gators using amsacrine are required to notify the NCI or WL/PD of all serious adverse reactions. Based on reports made to NCI and WL/PD and published reports, we have reviewed in detail the cardiac abnormalities associated with amsacrine administration. In this survey, the term amsa-

crine refers to the lactate salt dissolved in N, Ndimethylacetamide (DMA), the formulation most widely used. A few patients have been

treated with the gluconate salt of amsacrine, and this aspect will be discussed later. MATERIALS AND METHODS Approximately 180 published reports of clinical trials involving amsacrine therapy were reviewed for instances of cardiotoxicity of any kind. All published specific cases were also collected. The authors of these reports were contacted to gather additional data about the cardiac problem. Seventy patients were identified who developed either acute or chronic cardiac abnormalities. We also evaluated all communications to NCI regarding amsacrine-associated cardiac problems and all reports made to WL/PD. Forty-five patients with cardiac problems were identified from these reports. In many of these instances, the investigators were contacted to obtain additional data.

Case Exclusions For the 70 published cases, two of us (R.B.W. and S.M.) reviewed the additional data provided by the authors of these publications, and chose to exclude 15 patients. Two of these patients had only sinus tachycardia as the cardiac abnormality, and this was not considered to be a meaningful problem nor could amsacrine be implicated as the cause. Four cases were excluded because it was difficult for both the investigators and reviewers to ascribe the problems to amsacrine alone. In the rest of the cases, the cardiac problem was temporally distant from amsacrine administration, and/or the clinical and pathologic findings indicated anthracycline-induced cardiomyopathy or other pathology as the cause of the cardiac abnormalities. Of the 45 unpublished cases, 18 were excluded (by R.B.W. and J.G.P.) for the same reasons as the 15 patients in publications. In addition, several of these patients were excluded because the toxicity they experienced was in the form of a hypersensitivity reaction, which is known to occur with amsacrine.40 Thus, a total of 82 patients (55 published and 27 unpublished cases) form the basis of this review. These cases were then analyzed as to age, sex, tumor type, prior anthracycline exposure, prior known heart disease, amsacrine dose and schedule, serum potassium levels temporally associated with the cardiac episode, type of cardiac problem, ECG findings, outcome, and cardiac pathology if available. The types of cardiac events related to amsacrine therapy fell into two general categories: acute arrhythmias and ECG abnormalities or cardiomyopathy/congestive failure. For this analysis, the patients were divided into these two major types of cardiotoxicity. Hypokalemia was defined as a serum potassium < 3.5 mEq/L, and the instrument findings were designated as abnormal by the reporting investigators according to their own criteria.

RESULTS Incidence

We have attempted to present an estimate of the incidence of cardiotoxic reactions associated with amsacrine from the published literature (Table 1) through August 1984. We have identified 5,340 patients treated with amsacrine and 65 cases of cardiotoxic events among those patients (references provided on request). It seems probable that the overall number of cases of serious cardiotoxicity is more accurate than the total number of patients treated, because the occurrence of a clinical reaction might spur publication, whereas many of the patients treated do not appear in the literature. Thus, the incidence figures for clinically manifested cardiotoxicity are probably high, because the number of such reactions is close to correct, but the total number of patients treated is probably low. Of the 5,340 patients, 683 were previously untreated. Five of these patients developed arrhythmia (0.7%) and two developed echocardiographic changes (0.3%), for a total incidence of amsacrine-related cardiotoxicity of 1.0% in this group of patients who had not received any other chemotherapy. There are many published reports of phase II trials (Table 1) in which it is specifically stated that the patients sustained no cardiac abnormalities.4 1-47 In addition, there are patients who had been previously treated with maximum doses of anthracyclines and received substantial doses of amsacrine, yet had no cardiac problems. 48 One patient"9 even had anthracycline-induced cardiomyopathy and heart failure and was treated with high amsacrine doses over some months without any worsening of her cardiac problem. A similar patient who had left ventricular hypertrophy, cardiomyopathy (not anthracycline induced), and ventricular premature contractions before beginning amsacrine therapy was reported to the NCI. Despite amsacrine therapy over 13 months, there were no acute or chronic cardiac abnormalities beyond those already present. Finally, even treatment with very high amsacrine doses (200 mg/m2 daily for three to five days) caused no cardiac problems in 17 patients.50-52 Thus, cardiac abnormalities associated with amsacrine seem to represent a sporadic problem with a generally low incidence.

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

WEISS ET AL

920 Table 1. Literature Reports of Cardiotoxicity Associated With Amsacrine Instrument Manifestations

Clinical Manifestations

No. of Patients With

Patients

Total No. of Arrhythmia Patients (%)

Congestive Heart Failure (%)

ECG Changes (%)

Other Abnormalities* (%)

Total Cardiotoxicity (%)

Previously treated Previously untreated Uncertain

4,443 683 214

29 (0.6) 5 (0.7) 5 (2.3)

13 (0.3) 0 0

10 (0.2) 0 0

1 (0.02) 2 (0.3) 0

53 (1.2) 7 (1.0) 5 (2.3)

Totals

5,340

39 (0.7)

13 (0.2)

10 (0.2)

3 (0.06)

65 (1.2)

*Echocardiographic and radionuclide scanning changes.

Arrhythmias and ECG Changes Forty-two of the 55 published cases and 22 of the 27 unpublished cases had either a documented acute arrhythmia, sudden death presumed to be due to an arrhythmia, or ECG abnormalities (Table 2). Among these 64 patients, the severity and character of the cardiac event ranged from prolongation of the QT interval and nonspecific ST-T wave changes to ventricular tachycardia and/or ventricular fibrillation. Thirty-one patients had a serious ventricular arrhythmia that resulted in cardiopulmonary arrest; two patients had only ventricular tachycardia. Fourteen of these patients died as a result of the arrhythmia or cardiac arrest (Table 2). The cardiac arrests occurred either while the drug was being infused or within four hours after the infusion was completed. In one of the unpublished cases, the patient had cardiac monitoring during the drug infusion, and no abnormalities were noted. Four hours later she had an arrest. Other acute abnormalities noted are listed in Table 2. The abnormalities were temporally related to the infusion of amsacrine. All but one of the arrhythmic episodes occurred within minutes to several hours after drug administration. Some recurred when repeated doses were administered. One patient had corrected QT interval prolongation's with each drug dose. He received amsacrine at monthly intervals over 3 years, and the abnormality occurred each time. Three other patients had repeat episodes of tachyarrhythmias with repeat amsacrine doses. When the more severe arrhythmias were first observed with this drug, some of the patients

were found to have hypokalemia, and this abnormality was suspected by Legha, Von Hoff, and their colleagues to be a contributing factor for these arrhythmias. 5,6 Of the 64 patients with rhythm and ECG disturbances, 54 had serum potassium levels measured just before and/or just after the amsacrine administration. Sixteen (30%) had hypokalemia; 38 (70%) patients had normal serum potassium levels. Of the 45 patients who had serious disturbances (frequent ventricular premature contractions, ventricular tachycardia/fibrillation, or cardiopulmonary arrest), 38 had serum potassium levels determined. Table 2. Electrocardiographic and Rhythm Abnormalities Related to Amasacrine Infusion in 64 Patients

Type of Abnormality Frequent VPC (usually multifocal) Ventricular tachycardia/fibrillation and/or sudden cardiac arrest SVT Atrial flutter and/or fibrillation Prolonged corrected QT interval ST segment elevation/T wave inversion T wave flattening/prominent U waves

Death Due to No. of AbnorPatients mality 11*

-

34t 10: 3 5§ 5 1

14 -

Abbreviations: VPC, ventricular premature contractions; SVT, supraventricular tachycardia. *Two patients had both SVT and VPCs. tOne patient had both prolonged QT interval and ventricular tachycardia. :One patient had both SVT and ST segment elevation. §One patient had both prolonged QT interval and ST elevation.

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

921

AMSACRINE-ASSOCIATED CARDIOTOXICITY

thracyclines for both published and unpublished cases. Three patients had total doses of doxorubicin and/or daunorubicin between 560 and 615 mg/m 2. The rest had doses below 550 mg/m2, and the median doses were well below this level. The patient group that had the most morbidity and mortality had a cumulative median dose of 325 mg/m 2.

Fourteen (37%) had hypokalemia and 24 (63%) had normal serum potassiums. At least five patients had a serum potassium determination both before and very soon after the amsacrine infusion associated with the cardiac abnormality. Four of these five patients had normal potassium levels before the amsacrine and hypokalemic levels afterwards; one had normal levels before and after. Four other patients had hypokalemic levels right after an arrhythmia but did not have a pretreatment potassium determination (for purposes of the overall analysis, these patients were considered to be hypokalemic at the time of the cardiac event). Forty-five (70%) of the 64 patients had prior treatment with anthracyclines, and in all but one of the patients, the total cumulative dose of each anthracycline administered was known (Table 3). Seventeen did not have such prior treatment, and for two the prior use of an anthracycline could not be reliably determined. Since amsacrine is used most often for treatment of acute leukemia, most patients were previously treated with daunorubicin and/or doxorubicin. Four were additionally treated with rubidazone. Two patients were treated with rubidazone alone. Three patients had undergone mediastinal irradiation. Table 3 lists the cumulative doses of anTable 3.

Cardiomyopathic Events

Eighteen patients developed pulmonary edema thought to be related to heart failure or abnormalities of cardiac function as determined by gated radionuclide scanning or echocardiographic testing. Fourteen of the patients had severe abnormalities (Table 4) and six died. All 14 developed marked congestive failure within 16 days of the last amsacrine dose. One patient developed pulmonary edema as soon as the first dose of amsacrine had been infused, and three patients within the next 36 hours. As far as can be determined, these patients did not have simple fluid overload. In ten patients the heart failure developed after the first dose or course of amsacrine; the rest had it by the second course, so it was not a cumulative dose effect. In one unpublished case, the patient happened to have a Swan-Ganz catheter in place when he

Prior Anthracycline Treatment and Cardiac Abnormality

No. of Patients With Known Prior Anthracycline Treatment: Median Total Dose (Range)

Type of Cardiac Abnormality Frequent ventricular premature contractions only Ventricular tachycardia/fibrillation, sudden cardiac arrest Supraventricular tachycardia/atrial arrhythmia Electrocardiographic abnormalities (other than arrhythmias)

No. of Patients Without Prior Anthracycline

6:230 mg/m2 (100-360 mg/m2)

2

23:325 mg/m2 (50-980 mg/m 2)*

11

9:325 mg/m 2 (225-640 mg/m 2 )*

3

6:425 mg/m2 (80-600 mg/m 2)*

1

Total

44

Congestive heart failure/pulmonary edema Echocardiographic or scan abnormality

11:300 mg/m 2 (75-580 mg/m 2) 2: (122 and 525 mg/m2)

3 2

13

5

Total

17

2

*Four patients had 600 to 700 mg/m of rubidazone making their total anthracycline dose numerically high. All other patients had a total dose < 615 mg/m 2 of doxorubicin and/or daunorubicin.

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

922

WEISS ET AL Table 4. Cardiac Events Related to Cardiomyopathy in 18 Patients

Type of Cardiac Abnormality Congestive heart failure/pulmonary edema Echocardiographic or radionuclide scan abnormality indicating reduced myocardial contractility Total

No. of Patients

Death Due to Abnormality

14

6

4 18

0 6

received amsacrine. During two separate drug infusions administered at daily intervals, the patient developed hypotension, bradycardia, and doubling of the pulmonary wedge pressure. Four patients developed abnormal cardiac function as determined by echocardiograms and/ or gated radionuclide scans. All four had stabilization or improvement with treatment and did not die from cardiac dysfunction. Eleven of the 14 patients with heart failure/ pulmonary edema had prior anthracycline treatment (Table 3). Five patients had cardiac function abnormalities related to amsacrine without prior anthracycline treatment. History of PriorHeart Disease All 82 cases were analyzed for a history of cardiac disease that might have influenced the development of their cardiac abnormalities. For six of the patients this information was not obtainable. Sixty patients had no prior heart disease; at least ten of these patients had normal cardiac function testing just before they were treated with amsacrine. Sixteen patients were known to have some prior cardiac abnormality. Four patients had an abnormal echocardiogram; two of these four developed electrical cardiac abnormalities and two developed congestive heart failure within 2 weeks after finishing the first amsacrine course. One patient had an abnormal ejection fraction on radionuclide cardiac scan and had a cardiac arrest after amsacrine administration. There were four patients who had mild congestive heart failure; three of these patients had cardiac arrests and one had ventricular fibrillation. Three patients had preexisting electrical disturbances (occasional premature concentrations, nonspecific ECG ab-

normalities, bundle branch block), and one patient each had a functional heart murmur, hypertension, and well-controlled arteriosclerotic heart disease. One patient had undergone a coronary artery bypass operation 8 years previously. Patient Age and Sex Ten of the 64 patients with rhythm and ECG abnormalities and 7 of the 18 patients with cardiomyopathic abnormalities were aged 16 years and younger. Forty-six (56%) of the 82 patients were males. Tumor Type The tumor for which amsacrine was being used was known in all 82 patients. Nine patients had lymphomas, 15 had various solid tumors, and the rest had various types of acute leukemia. Amsacrine Dose and Vehicle The amsacrine doses were variable and reflected the general use of a single every-3-week dose schedule for solid tumors and a higher dose daily schedule for three to seven days in acute leukemias. Most of the cardiac events occurred after one dose or one course of amsacrine. There was no evidence of a cumulative dose effect in most patients. There were only two patients21 who had repetitive amsacrine doses over a period of time in which there is a possibility of a cumulative dose effect. Both developed an abnormal radionuclide cardiac scan at total amsacrine doses of 580 mg/m 2 and 920 mg/m 2, respectively. The drug vehicle used most often was DMA, and this agent has been suggested as a possible factor in the cardiac toxicity. 6 Amsacrine gluconate was thus developed and investigated to determine if it would be less cardiotoxic than the DMA formulation. One patient" had transient supraventricular tachycardia and ventricular premature contractions with each dose, and three patients developed congestive heart failure3 9 with amsacrine gluconate. Outcome and Pathology As indicated in Tables 2 and 4, a total of 20 patients succumbed to the cardiac event related to amsacrine. The rest stabilized, had no recurrence with further amsacrine, had no further amsacrine treatment, or tolerated the cardiac event

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

923

AMSACRINE-ASSOCIATED CARDIOTOXICITY

despite its recurrence. One patient had a pacemaker inserted after developing ventricular tachycardia and asystole in conjunction with amsacrine. The ventricular arrhythmia occurred again when another course of the drug was administered. One patient was cardioverted for atrial flutter, but the atrial flutter recurred when amsacrine was administered again. 24 Six patients received more amsacrine and had no recurrence of the cardiac rhythm problems; one patients' had 11 more doses of amsacrine without problems. Two patients,'8 who had corrected QT interval prolongation, had the same abnormality with each subsequent drug dose. There was no progression to more serious abnormalities. However, one patient did progress to ventricular tachycardia/fibrillation after initially having only a prolonged corrected QT interval.3" One patient who developed congestive heart failure was controlled with treatment during subsequent amsacrine doses. When the amsacrine was stopped because of tumor progression, the indications of heart failure improved. There were 12 patients who had autopsies after dying of either the amsacrine-related event or their disease and/or sepsis (Table 5). One patient 9 with congestive failure had foci of cardiac necrosis, but there was no vacuolization typical of anthracycline-induced cardiac pathology. This Table 5.

Cardiac Pathology in 12 Patients Who Died Soon After Amsacrine Treatment

Cardiac Event Cardiac arrest

No. of Patients 6

Cardiac Findings at Autopsy Normal heart: 3 Old small infarction: 1 Coronary artery disease (no fresh

ECG abnormalities Abnormal echocardiogram Congestive heart failure

1 1 4

infarcts): 1 Focal myocardial "congestion": 1 Petechial hemorrhage Normal heart Normal heart: 1 Coronary artery disease (no fresh

infarcts): 1 Multiple foci of cardiac necrosis without vacuolization: 1 Petechial hemorrhage: 1

patient had been treated previously with a 450 mg/m2 total dose of doxorubicin and developed congestive failure after the first dose of amsacrine. The rest of the patients had either no cardiac pathology by light microscopy or had incidental cardiac abnormalities typical of the age and disease population under study. DISCUSSION

Amsacrine has been administered to over 6,000 patients, yet we were able to collect only 82 cases in which cardiac abnormalities were related to the drug. Some of the abnormalities identified are subtle, such as T wave inversion and prolongation of the corrected QT interval on ECG. These findings were observed when the patient had continuous cardiac monitoring during drug administration. There may well be underrecognition and underreporting of such instrument manifestations. In fact, a study by Shinar and Hasin"5 provides strong evidence that such underrecognition does occur. These investigators found prolongation of the corrected QT interval after amsacrine administration in all 12 patients studied. It was reversible within 24 hours. Prominent U waves and flattening of the T waves were also observed. More life-threatening abnormalities such as ventricular arrhythmias and cardiac arrest are not likely to go unrecognized or be ascribed to nondrug-related conditions. Therefore, the fact that we were able to identify only 45 cases of such serious arrhythmias suggests that they are rare, especially since there are many patient series in which no cardiac events were observed, including ones where high drug doses were administered. These facts support the notion that serious cardiac toxicity associated with amsacrine is uncommon. The fact that some patients can have cardiac disease already and be treated with amsacrine with no adverse effects also supports this conclusion. As with anthracyclines, there are two forms of cardiac toxicity associated with amsacrine. One, the more common, is the alteration of cardiac electrical physiology leading to a spectrum of effects from ECG changes to atrial and ventricular tachyarrhythmias. The other is the development of cardiomyopathy and congestive heart failure. The observed arrhythmic events appear to be

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

924

WEISS ET AL

related to the administration of amsacrine. All but one occurred within minutes to several hours after the patient received the drug. However, Mayernik et a15 4 showed that patients undergoing cancer chemotherapy may have brief episodes of atrial and ventricular premature contractions unrelated to any drug administration. None of the cases in our analysis had cardiac monitoring before treatment with amsacrine, so it cannot be determined how many, if any, of the episodes of arrhythmia were not drug-induced. The cardiomyopathic phenomena manifested by development of echocardiographic and cardiac scan abnormalities could have causes other than amsacrine. The type of patient treated with amsacrine is one who is ill with advanced carcinoma or leukemia. With leukemia, the patient has many severe ancillary medical problems, such as systemic sepsis, and it is possible that progressively abnormal cardiac testing is not related to amsacrine. Of the patients who had these cardiac manifestations, two had acute leukemia and two had mesothelioma. The two patients with leukemia were septic at some time during the sequential cardiac testing. What role this fact played in cardiac dysfunction is speculative. The other cardiomyopathic phenomenon is the onset of congestive failure/pulmonary edema. All 14 patients with these problems had the onset of failure within 2 weeks, and four had onset within 36 hours of receiving amsacrine. This close temporal relationship suggests that they were related to amsacrine, rather than a coincidental event. The one patient who fortuitously had a Swan-Ganz catheter in place provides the strongest support that amsacrine can be associated with cardiac dysfunction. Each time amsacrine was administered the patient developed hypotension, slowing of the pulse, and elevation of the wedge pressure. Some cancer chemotherapeutic agents can precipitate pulmonary edema by a noncardiogenic means.55 5s6 The mechanism for this may be a drug-induced alveolitis that results in alveolar edema. It is possible that some of the patients in the present series had the onset of pulmonary edema mediated by such a pulmonary effect. However, the sequence of events in the one patient described previously tends to refute this possibility. Cardiac arrest occurred in 26 patients, and 14 died. All of these events occurred within four

hours of receiving amsacrine. Although such arrhythmias are uncommon, it would be prudent to have patients under medical supervision during and for several hours after amsacrine administration. Some investigators have put patients on continuous cardiac monitoring during amsacrine infusion, but this seems unnecessary because of the rarity of the severe arrhythmias and the fact that they do not necessarily come only during drug infusion. One patient had normal cardiac monitoring during drug infusion, yet had a cardiac arrest four hours later. Hypokalemia can have cardiac effects primarily during repolarization, and arrhythmias can occur when profound hypokalemia is present." When hypokalemia was discovered in some of the first patients to sustain serious ventricular arrhythmias, it was suspected of being a risk factor for amsacrine-related problems. The fact that 14 of the 45 patients who had serious cardiac disturbances had hypokalemia supports this theory. However, 24 patients had serious problems despite having normal pretreatment potassium levels. It is of interest that at least four patients developed hypokalemia right after amsacrine administration. Four other patients had hypokalemia right after the amsacrine infusion but had no pretreatment levels measured. Further study of serum potassium levels temporally related to amsacrine administration seems worthwhile. Data on the incidence of hypokalemia in the population not sustaining cardiac abnormalities related to amsacrine are not available. Another factor that could heighten the risk of cardiac problems is prior treatment with anthracyclines. Anthracycline use appeared not to be a factor, because 16 patients among those with an arrhythmia had not received anthracyclines, and even among those who had, the cumulative doses were moderate. Eleven of the 14 patients with congestive failure had received anthracycline treatment, but the cumulative doses also were moderate. Since anthracyclines are part of the standard treatment of acute leukemia, a patient receiving amsacrine usually will have been treated with these agents, but there is no strong evidence that such prior treatment makes the heart susceptible to amsacrine. The possibility of other underlying cardiac disease increasing the risk of amsacrine-related toxicity probably can be discounted. Most of the

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

AMSACRINE-ASSOCIATED CARDIOTOXICITY

patients had no known cardiac disease and among those who did, the degree of the problems was low. Patients with leukemia sustain many complications and receive therapies that possibly influence susceptibility to cardiac events related to amsacrine. It was not possible to analyze for such myriad possibilities in our review, and thus their effect in the occurrence of cardiac abnormalities is unknown. There was an approximately equal distribution according to sex, and thus gender apparently has no bearing on cardiac toxicity. There appears to be a greater than expected representation of pediatric-age patients among the 82 patients, especially among the group having cardiomyopathy where 39% were 16 years old or younger. The total number of children treated with amsacrine in relation to the total number of adults is not known, so no definite statement about children being more susceptible to amsacrine can be made. It is known that daunorubicin causes cardiotoxicity in children more frequently than in adults,"5 and amsacrine may be similar in this regard. The anthracyclines cause a cardiomyopathy produced by repetitive drug doses. Amsacrine does not appear to have a similar cumulative dose effect on the heart. Of the patients who developed cardiomyopathic events, only two had progressively abnormal ejection fractions on radionuclide cardiac scanning. Twenty patients died of the amsacrine-related cardiac abnormality. A large proportion (41%) of patients who had serious ventricular tachyarrhythmias or cardiac arrest died. All of the other patients, including the 11 with ventricular premature contractions, survived the cardiac problem. Six of the 18 patients with cardiomyopathy died of congestive heart failure within a short period of its onset. The rest later died of their cancer and/or sepsis, and amsacrine seemed to play no role in the death. In those 12 patients who had autopsies, only one patient had any abnormalities suggestive of drug toxicity. Since this patient also had been treated with doxorubicin, it is difficult to say whether the histologic features were amsacrine or doxorubicin induced. However, there was no myocyte vacuolization typical of damage due to doxorubicin. Five patients had normal hearts morphologically.

925

The cardiac damage produced by anthracyclines is recognized as being cumulative-dose dependent and mediated by myocytolysis. The mechanism of amsacrine-related toxicity is not as clear. During preclinical toxicology testing of this agent by Will et al, 59 there was little evidence of cardiac effect in rabbits. An identical evaluation of an equimyelotoxic dose of doxorubicin in the same study showed consistent ECG and cardiac pathologic abnormalities.?9

However, D'Alessandro et a160 studied amsacrine effects on rabbit hearts at higher doses and observed a variety of acute ECG abnormalities. Hemiblock, first degree A-V block, ventricular premature contractions, supraventricular tachycardia, atrial flutter, intraventricular conduction delay, ventricular tachycardia, and second degree A-V block were seen at all doses tested. These ECG changes appeared immediately or within five minutes of amsacrine administration. Of note is the fact that similar testing of amsacrine vehicle solution (DMA) failed to cause any cardiac abnormalities. Studies by Hamlin et a16' in dogs using amsacrine at the toxic dose high (3 mg/kg), lethal dose (6 mg/kg), and supralethal dose (24 mg/kg) showed that the drug had marked effects on atrioventricular and intraventricular conduction. First degree A-V block, prolongation of the QRS interval, and prolongation of the QT interval not due merely to prolongation of ventricular activation were frequently seen in dogs administered the lethal and supralethal amsacrine doses. There were also marked ST-T wave changes with increased duration and amplitude of the T waves in the dogs administered the high dose. Other significant cardiac changes observed at the highest dose were marked sinus bradycardia, decrease in cardiac output, and increase in pulmonary vascular resistance. One dog died within 30 minutes of receiving the high dose, presumably of a cardiac arrest. Although studies such as this one indicate the range of cardiac events related to amsacrine, they are difficult to evaluate regarding their relevance to the clinical setting, because there was no anthracycline control and extremely high amsacrine doses were used. Lowe 62 tested the effect of amsacrine on isolated rat heart myocytes and found that amsacrine was approximately one tenth as potent as the

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

926

WEISS ET AL

anthracyclines in ability to inhibit myocyte contraction. Only pure amsacrine was used in this study and not the clinical formulation containing DMA. Thus, the observed drug effects could not be due to vehicle. All these experiments provide evidence for an amsacrine cardiac effect in animals. Both electrophysiologic changes and contractility decrease occur. Most of the abnormalities observed in animals were noted in one or more patients in this present analysis. The cardiac effect of amsacrine is not as potent in animals as that of the anthracyclines in either form of cardiac abnormality: electrophysiologic or myocontractility. The same appears true in the clinical situation. Weiss et al'8 originally hypothesized that QT interval prolongation is a common and overlooked abnormality produced by amsacrine. These investigators further suggested that delayed repolarization produced by amsacrine may be an initiating factor of the tachyarrhythmias seen in some patients. The subsequent studies of Schwartz et a138 and Shinar and Hasin 53 support both hypotheses. Schwartz et aPl described a patient who initially had a prolonged QT interval on ECG from amsacrine and then progressed to a ventricular tachycardia. Shinar and Hasin 53 showed that QT interval prolongation is frequently observed, if one carefully looks for it. What factors cause a minority of patients to progress to tachyarrhythmia after amsacrine administration are unknown. One possibility is that hypokalemia may act in concert with amsacrine to precipitate arrhythmia. However, since approximately two thirds of the patients with serious arrhythmias had a normal serum potassium before receiving amsacrine, this is not necessarily a factor. From our retrospective analysis, we conclude that amsacrine-related cardiac toxicity can lead to both ventricular and atrial arrhythmias and acute congestive failure. The risk of these events

appears much lower than that for the anthracyclines. There is little or no cumulative dose ef-

fect, and any of these cardiac events may occur with the initial amsacrine dose. Although there is some uncertainty about the fact, children appear to have a higher risk of cardiac problems for

unknown reasons. The presence of hypokalemia may be a risk factor for serious cardiac events, and thus a serum potassium should be determined before an amsacrine dose is administered. However, a normal potassium level does not preclude the possibility of cardiac problems. There

is no evidence that any componerit of the formulation other than amsacrine is associated with the

observed cardiac abnormalities, either in patients or experimental animals. The mechanism for these effects at the cellular and molecular levels remains to be determined. No methods for preventing amsacrine-related toxicity have yet been found. Both these issues are worthy of further study. ACKNOWLEDGMENT The authors thank the following physicians and others for being generously helpful in providing information on their patients treated with amsacrine: Muhyi Al-Sarraf, Zalmen A. Arlin, John W. Athens, Emilio Bajetta, Alfred A. Bartolucci, Ellin Berman, Gerald P. Bodey, Phillip Bonomi, Goronwy O. Broun, C. Patrick Bums, Robert W. Carlson, Delvyn C. Case, Peter A. Cassileth, Ralph G. Cobcroft, Cornelius J. Cornell, Dennis B. Cornfield, Juan C. Dupont, Robert T. Eagan, Rhett K. Fredric, Robert Peter Gale, Stuart A. Grossman, Eva Hvizdala, S. Benham Kahn, Vita J. Land, Richard Larson, H. Jeffrey Lawrence, Sewa S. Legha, Howard E. Lessner, T.A. Lister, John Loughner, Victor Lui, James S. Malpas, John C. Marsh, Orlando Martelo, David Martz, Nazli Gad-el-Mawla, Peter McLaughlin, Kenneth C. Micetich, Charles F. Miller, George A. Omura, Frank J. Panettiere, Richard B. Patterson, Santiago Pavlovsky, David J. Perry, Bruce A. Peterson, Julia E. Pfile, Bruce R. Piccone, Bruce G. Raphael, Mary J. Retzer, Saul E. Rivkin, Anna Rossi, Harold R. Silberman, Dominic A. Solimando, Laurel J. Steinherz, Donald L. Sweet, Charlotte Tan, Paul J. Thomas, David A. Van Echo, Enrique Vl6ez-Garcia, Paul C. Vincent, W. Ralph Vogler, Daniel D. Von Hoff, Daniel A. Vorobiof, and Elliott F. Winton. The authors also thank William Soper for editorial assistance.

REFERENCES 1. Cain BF, Atwell GJ, Seelye RN: Potential antitumour agents. X. Bisquatemary salts. J Med Chem 12:199-206, 1969 2. Cain BF, Seelye RN, Atwell GJ: Potential antitumor agents. 14. Acridylmethanesulfonanilides. J Med Chem 17: 922-930, 1974 3. Gormley PE, Sethi VS, Cysyk RL: Interaction of 4'-(9acridinylamino) methanesulfon-m-anisidide with DNA and inhi-

bition of oncomavirus reverse transcriptase and cellular nucleic acid polymerases. Cancer Res 38:1300-1306, 1978 4. Tokaz LK, Von Hoff DD: The cardiotoxicity of anticancer agents, in Perry MC, Yarbro JW (eds): Toxicity of Chemotherapy. Orlando, Fla, Grune & Stratton, 1984, pp 199-226 5. Legha SS, Latreille J, McCredie KB, et al: Neurologic and cardiac rhythm abnormalities associated with 4'-(9-acridinyla-

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

AMSACRINE-ASSOCIATED CARDIOTOXICITY mino) methanesulfon-m-anisidide (AMSA) therapy. Cancer Treat Rep 63:2001-2003, 1979 6. Von Hoff DD, Elson D, Polk G, et al: Acute ventricular fibrillation and death during infusion of 4'-(9-acridinylamino) methanesulfon-m-anisidide (AMSA). Cancer Treat Rep 64: 356-358, 1980 (letter) 7. Falkson G: Multiple ventricular extrasystoles following administration of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA). Cancer Treat Rep 64:358, 1980 (letter) 8. Arlin ZA, Flomenberg N, Gee TS, et al: Treatment of acute leukemia in relapse with 4'(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in combination with cytosine arabinoside and thioguanine. Cancer Clin Trials 4:317-321, 1981 9. Slevin ML, Shannon MS, Prentice HG, et al: A phase I and II study of m-AMSA in acute leukaemia. Cancer Chemother Pharmacol 6:137-140, 1981 10. Valdivieso M, Stroehlein JR, Bedikian AY, et al: Phase II clinical evaluation of intravenous 4'-(9-acridinylamino)methanesulfon-m-anisidide in colorectal cancer. Am J Clin Oncol 6:39-44, 1983 11. Omura GA, Winton EF, Vogler WR, et al: Phase II study of amsacrine gluconate in refractory leukemia. Cancer Treat Rep 67:1131-1132, 1983 12. Boccia R, Zighelboim i, Champlin RE, et al: AMSA: A phase II trial in resistant and recurrent acute myelogenous leukemia. Med Pediatr Oncol 12:178-179, 1984 13. Winton EF, Hearn EB, Vogler WR, et al: Amsacrine in refractory adult acute leukemia: A pilot study of the Southeastern Cancer Study Group. Cancer Treat Rep 67:977-980, 1983 14. Miller CF, Rajdev N: Acute ECG changes associated with AMSA treatment. Cancer Treat Rep 66:1678-1680, 1982 (letter) 15. Foldes JA, Yagil Y, Kornberg A: Ventricular fibrillation, hypokalemia, and AMSA therapy. Ann Intern Med 96: 121-122, 1982 (letter) 16. Bonomi P, Blessing JA, Sedlacek TV, et al: Phase II trial of AMSA in patients with advanced or recurrent squamous cell carcinoma of the cervix: A Gynecology Oncology Group study. Cancer Treat Rep 67:197-198, 1983 17. Riela AR, Kimball JC, Patterson RB, et al: Cardiac arrhythmia associated with AMSA in a child: A Southwest Oncology Group study. Cancer Treat Rep 65:1121-1123, 1981 18. Weiss RB, Moquin D, Adams JD, et al: Electrocardiographic abnormalities induced by amsacrine. Cancer Chemother Pharmacol 10:133-134, 1983 19. McLaughlin P, Salvador PG, Cabanillas F, et al: Ventricular fibrillation following AMSA. Uncomplicated retreatment following correction of hypokalemia. Cancer 52:557-558, 1983 20. Kahn SB, Sklaroff R, Lebedda J, et al: 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and 5-azacytidine (AZA) in the treatment of relapsed adult acute leukemia. Am J Clin Oncol 6:493-502, 1983 21. Vorobiof DA, Iturralde M, Falkson G: Amsacrine cardiotoxicity: Assessment of ventricular function by radionuclide angiography. Cancer Treat Rep 67:1115-1117, 1983 22. Omura GA, Bartolucci AA, Lessner HE, et al: Phase II evaluation of amsacrine in colorectal, gastric, and pancreatic carcinomas: A Southeastern Cancer Study Group trial. Cancer Treat Rep 68:929-930, 1984 23. Inamasu M, Oishi N, Chen T, et al: Phase II trial of

927 amsacrine in pancreatic carcinoma. A Southwest Oncology Group study. Cancer Treat Rep 68:1411-1412, 1984 24. Winton EF, Hearn EB, Martelo O, et al: Sequentially administered 5-azacitidine and amsacrine in refractory adult acute leukemia: A phase I-II study of the Southeastern Cancer Study Group. Cancer Treat Rep 69:965-969, 1985 25. Lawrence HJ, Ries CA, Reynolds RD, et al: AMSA-A promising new agent in refractory acute leukemia. Cancer Treat Rep 66:1475-1478, 1982 26. Steinherz LJ, Steinherz PG, Mangiacasale D, et al: Cardiac abnormalities after AMSA administration. Cancer Treat Rep 66:483-488, 1982 27. De Lena M, Rossi A, Bonadonna G: Phase II trial of AMSA in refractory breast cancer. Cancer Treat Rep 66: 403-404, 1982 28. Al-Sarraf M: Combination of cyclophosphamide, Adriamycin and cis-platinum (CAP) versus m-AMSA in patients with advanced transitional bladder cancers. Proc Am Soc Clin Oncol 1:105, 1982 (abstr) 29. Dupont J, Garay G, Scaglione P, et al: A phase II trial of M-AMSA in acute leukemia. Proc Am Soc Clin Oncol 22:477, 1981 (abstr) 30. Marcus FS, Friedman MA, Resser KJ, et al: Treatment of resistant breast cancer by combination chemotherapy with AMSA, prednisone, and chlorambucil (APC). Proc Am Soc Clin Oncol 22:438, 1981 (abstr) 31. Nichols WC, Eagan RT, Frytak S, et al: Phase II evaluation of AMSA in patients with metastatic lung cancer. Cancer Treat Rep 64:1383-1385, 1980 32. Weil M, Auclerc MF, Schaison G, et al: Activit6 clinique de la m-Amsa et de l'association de m-Amsa et de cytosine arabinoside. Nouv Presse Med 11:2911-2914, 1982 33. Cassileth PA, Lyman GH, Bennett JM, et al: High-dose amsacrine (AMSA) therapy of relapsed and refractory adult acute non-lymphocytic leukemia. A phase II study. Am J Clin Oncol 7:361-363, 1984 34. Legha SS, Keating MJ, McCredie KB, et al: Evaluation of AMSA in previously treated patients with acute leukemia: Results of therapy in 109 adults. Blood 60:484-490, 1982 35. Case DC: m-AMSA: Phase II trial in advanced lymphoma and leukemia. Am J Clin Oncol 7:357-360, 1984 36. Krischer J, Land VJ, Civin CI, et al: Evaluation of AMSA in children with acute leukemia. A Pediatric Oncology Group study. Cancer 54:207-210, 1984 37. Micetich KC, Zwelling LA, Gormley P, et al: Phase I-II study of m-AMSA administered as a continuous infusion. Cancer Treat Rep 66:1813-1817, 1982 38. Schwartz CL, Bender KS, Burke PJ, et al: QT interval prolongation and cardiac dysrhythmia in a patient receiving amsacrine. Cancer Treat Rep 68:1043-1044, 1984 39. Figueroa-Casas JL, Velez-Garcia E, Grillo-Lopez AJ, et al: Cardiomyopathy with amsacrine gluconate. Clin Res 30: 746A, 1982 (abstr) 40. Perry DJ, Weiss RB, Hoth DF: Hypersensitivity reactions to amsacrine. Cancer Treat Rep 69:199-201, 1985 41. Ratanatharathorn V, Drelichman A, Sexon-Porte M, et al: Phase II evaluation of 4'-(9-acridinylamino)-methanesulfonm-anisidide (AMSA) in patients with advanced head and neck cancers. Am J Clin Oncol 5:29-32, 1982 42. Ettinger DS, Day R, Ferraro JA, et al: A randomized phase II study of m-AMSA (NSC 249992) and neocarzinostatin

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.

928

WEISS ET AL

(NSC 157365) in non-small cell bronchogenic carcinoma. An Eastern Cooperative Group study. Am J Clin Oncol 6:167-170, 1983 43. Legha SS, Blumenschein GR, Buzdar AU, et al: Phase 11 study of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in metastatic breast cancer. Cancer Treat Rep 63: 1961-1964, 1979 44. Schneider RJ, Woodcock TM, Yagoda A: Phase II trial of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in patients with metastatic hypernephroma. Cancer Treat Rep 64:183-185, 1980 45. Legha SS, Hall SW, Powell KC, et al: Phase II study of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) in metastatic melanoma. Cancer Clin Trials 3:111-114, 1980 46. Bukowski RM, Leichman LP, Rivkin SE: Phase II trial of m-AMSA in gallbladder and cholangiocarcinoma: A Southwest Oncology Group Study. Eur J Cancer Clin Oncol 19: 721-723, 1983 47. De Jager R, Siegenthaler P, Cavalli F, et al: Phase II study of amsacrine in solid tumors: A report of the EORTC Early Clinical Trial-Group. Eur J Cancer Clin Oncol 19:289-293, 1983 48. Legha SS, Gutterman JU, Hall SW, et al: Phase I clinical investigation of 4'-(9-acridinylamino)methanesulfon-m-anisidide (NSC 249992), a new acridine derivative. Cancer Res 38:3712-3716, 1978 49. Fanucchi MP, Arlin ZA: Successful treatment of a patient with acute nonlymphoblastic leukemia (ANLL) and anthracycline cardiomyopathy with 4' (9-acridinylamino)methanesulfon-m-anisidide (AMSA). Cancer Chemother Pharmacol 10: 27-28, 1982 50. Goldman A, Malpas JS: Phase I and II study of AMSA in childhood tumours. Cancer Chemother Pharmacol 9:53-56, 1982 51. Tannir N, Spitzer G, Schell F, et al: Phase II study of

high-dose amsacrine (AMSA) and autologous bone marrow transplantation in patients with refractory metastatic breast cancer. Cancer Treat Rep 67:599-600, 1983 52. Zander AR, Vellekoop L, Dicke KA, et al: High-dose AMSA and autologous bone marrow transplantation in relapsed acute leukemia. Cancer Treat Rep 66:1991-1992, 1982 53. Shinar E, Hasin Y: Acute electrocardiographic changes induced by amsacrine. Cancer Treat Rep 68:1169-1172, 1984 54. Mayemik D, Stevenson T, Neidhart J: Acute cardiac arrhythmias with phase I and II agents. Proc Am Soc Clin Oncol 1:14, 1982 (abstr) 55. Haupt HM, Hutchins GM, Moore GW: Ara-C lung: Noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. Am J Med 70:256-261, 1981 56. Bernstein ML, Sobel DB, Wimmer RS: Noncardiogenic pulmonary edema following injection of methotrexate into the cerebrospinal fluid. Cancer 50:866-868, 1982 57. Kaplan NM: Our appropriate concern about hypokalemia. Am J Med 77:1-4, 1984 (editorial) 58. Von Hoff DD, Rozencweig M, Layard M, et al: Daunomycin-induced cardiotoxicity in children and adults. Am J Med 62:200-208, 1977 59. Will J, Splitter G, Lalich J, et al: Adriamycin cardiotoxicity: A comparison with m-AMSA (NSC #249992). Document #PB 81-110421. Springfield, Va, National Technical Information Service, 1980 60. D'Alessandro N, Gebbia N, Crescimanno M, et al: Effects of amsacrine (m-AMSA), a new aminoacridine antitumor drug, on the rabbit heart. Cancer Treat Rep 67:467-474, 1983 61. Hamlin RL, Pipers FS, Nguyen K, et al: Acute cardiovascular effects of acridinyl anisidide (NSC-249992) following continuous intravenous infusion to anesthetized beaglehounds. Document #PB 264 120. Springfield, Va, National Technical Information Service, 1976 62. Lowe MC: In vitro evaluation of the cardiotoxic potential of AMSA. Cancer Treat Rep 66:1571-1573, 1982

Information downloaded from jco.ascopubs.org and provided by at DFG on December 17, 2010 from 141.2.62.70 Copyright © 1986 American Society of Clinical Oncology. All rights reserved.