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September 24, 2002; 59 (6) Articles

Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS

R. G. Ghalie, G. Edan, M. Laurent, E. Mauch, S. Eisenman, H. P. Hartung, R. E. Gonsette, M. D. Butine, D. E. Goodkin
First published September 24, 2002, DOI: https://doi.org/10.1212/WNL.59.6.909
R. G. Ghalie
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G. Edan
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M. Laurent
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E. Mauch
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S. Eisenman
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H. P. Hartung
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R. E. Gonsette
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M. D. Butine
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D. E. Goodkin
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Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS
R. G. Ghalie, G. Edan, M. Laurent, E. Mauch, S. Eisenman, H. P. Hartung, R. E. Gonsette, M. D. Butine, D. E. Goodkin
Neurology Sep 2002, 59 (6) 909-913; DOI: 10.1212/WNL.59.6.909

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Abstract

Background: Mitoxantrone (MITO) is associated with dose-related cardiotoxicity when administered concomitantly with other cytotoxic agents with or without radiotherapy for leukemia and solid tumors.

Objective: To review observed cardiotoxicity of single-agent MITO therapy for MS.

Methods: Records of 1,378 patients from three clinical trials of MITO treatment for MS were reviewed for signs and symptoms of cardiac dysfunction and left ventricular ejection fraction (LVEF) results. Duration of follow-up was a median of 29 months (4,084 patient-years).

Results: No patients experienced congestive heart failure (CHF) before treatment. Cumulative MITO doses ranged from 2 to 183 mg/m2 (mean 60.5 mg/m2, median 62.5 mg/m2), and 141 patients received >100 mg/m2. Two of 1,378 patients experienced CHF after initiating MITO therapy. Of 1,378 patients, 779 completed baseline and scheduled follow-up LVEF testing. Baseline LVEF was >50% in all 779 patients. Seventeen of 779 patients had asymptomatic LVEF of <50% (incidence proportion = 2.18%, 95% CI = 1.28 to 3.47%). Although the incidence of asymptomatic LVEF of <50% was not significantly related to monthly versus 3-monthly therapy, duration of therapy, age, or gender, asymptomatic LVEF of <50% trended higher with a cumulative dose of ≥100 mg/m2 (5.0%) than with <100 mg/m2 (1.8%) (p = 0.06).

Conclusions: The observed incidence of CHF in patients with MS who received a mean cumulative dose of 60.5 mg/m2 MITO was <0.20%. Continued monitoring of patients with MS who are receiving MITO is needed to determine whether the incidence of CHF increases with higher cumulative MITO doses and prolonged follow-up.

Cardiac toxicity has been reported in cancer patients who receive mitoxantrone (Novantrone; Immunex Corp., Seattle, WA [MITO]) as an immunosuppressive chemotherapeutic agent.1-5⇓⇓⇓⇓ MITO-associated cardiotoxicity may be characterized by changes in EKG, indicating possible tachycardia and arrhythmia, asymptomatic decrease in measures of left ventricular ejection fraction (LVEF), or symptomatic congestive heart failure (CHF). The increased risk of cardiotoxicity is associated with higher cumulative doses of MITO, prior treatment with anthracyclines, prior mediastinal radiotherapy, and pre-existing cardiovascular diseases.1 The mechanisms of MITO-associated cardiotoxicity are not completely understood but are likely due to the formation of iron chelates that promote formation of reactive oxygen intermediates that mediate damage of myocardial tissue.6 Histologic endomyocardial changes associated with MITO administration include dilatation of the sarcoplasmic reticulum with vacuole formation and myofibrillar dropout.7

MITO is approved in the United States for the treatment of worsening relapsing–remitting (RR), secondary progressive (SP), and progressive relapsing (PR) MS. Unlike patients with leukemia and solid tumors who generally receive MITO in combination with other cytotoxic agents with or without radiotherapy, patients with MS are treated with MITO as a single-agent disease-modifying therapy. We undertook this study because the risk of cardiac toxicity after single-agent MITO therapy for MS has not been rigorously examined.

Patients and methods.

Patient data for this analysis were obtained from three studies. The first was a Phase 3, multicenter, randomized, controlled clinical trial of MITO in MS (MIMS).8 The MIMS study compared 12 mg/m2 MITO (n = 60), 5 mg/m2 MITO (n = 64), and placebo (methylene blue) (n = 64) administered IV every 3 months for up to 2 years in patients with worsening RRMS and SPMS. The study protocol required a final clinical assessment 1 year after therapy was discontinued. Tests of LVEF (echocardiogram or radionuclide scan) were performed at baseline and at 12, 24, and 36 months after initiating assigned therapy. To be eligible for enrollment, baseline LVEF had to be >50%. Patients were withdrawn from treatment if, at any time, LVEF decreased to <50% or by ≥10% of the baseline LVEF.

The second study was an ongoing French multicenter, open-label trial of MITO in MS. This study was conducted at 12 French MS centers and was coordinated by the Clinique Neurologique of the University Hospital Pontchaillou in France.9 Eight hundred two patients were treated with open-label MITO. All patients received 20 mg (approximately 12 mg/m2) IV MITO preceded by 1 g IV of methylprednisolone. Of the 802 patients, 107 received MITO every third month and 695 received MITO monthly for 6 months. Of the 695 patients who received treatment monthly, 182 continued to receive 20 mg MITO every third month after completing the 6-month induction phase. All 802 patients had LVEF testing before initiation of therapy, and 655 of 802 patients had additional LVEF testing at 6, 24, and 60 months. MITO therapy was discontinued if LVEF decreased to <50%.

The third study was performed at the Clinic of Neurologic Disease of Ulm University in Germany.10 In this study, 452 patients with worsening RRMS, SPMS, and PPMS were treated with 12 mg/m2 open-label MITO every third month. The treatment and observation period was from November 1988 to September 1998. LVEF was measured before treatment was initiated, and only patients with an LVEF of >50% entered the study. The protocol did not require follow-up testing of LVEF.

Statistical methods.

The duration of follow-up was measured in patient-years, which was calculated from initiation of MITO therapy to last contact with the patient. The 95% exact CI of the incidence proportion of cardiac events and of LVEF of <50% were calculated assuming a binomial distribution. Fisher’s exact test was used in contingency table analyses to compare proportions. For stepwise logistic regression modeling, a forward substitution/backward elimination method was used, based on χ2 p values. Statistical analyses were performed using SAS11 and StatXact12 software programs.

Results.

The design and demographics of the three MITO studies are summarized in table 1, and the incidences of CHF and asymptomatic LVEF of <50% in the three studies are summarized in table 2.

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Table 1 Design and demographics of three MITO studies in MS

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Table 2 Incidence of CHF and asymptomatic LVEF of <50% in three MITO studies in MS

Phase 3 trial of MITO in MS (MIMS trial).

Of the 124 patients who received MITO in the MIMS trial, 64 received 5 mg/m2 MITO and 60 received 12 mg/m2 MITO every 3 days monthly for up to 2 years. For this cohort of 57 men and 67 women, the mean age was 39.9 years (range 21 to 55 years) and mean Expanded Disability Status Scale (EDSS) score was 4.55 (range 3.0 to 6.0). The mean cumulative dose of MITO was 61 mg/m2, and the mean duration of follow-up was 32 months. None of the MITO or placebo recipients enrolled in this study experienced clinically significant cardiac dysfunction. Four MITO recipients had asymptomatic reduction of LVEF to <50% (none to <40%). Two of these four patients had asymptomatic LVEF of <50% at month 12 at cumulative doses of 20 mg/m2 (four doses) and 48 mg/m2 (four doses). Both patients remained asymptomatic and had one additional infusion, yielding cumulative doses of 25 and 60 mg/m2 with normal repeat tests of LVEF at month 15 (69%) and month 24 (60%). The other two patients remained asymptomatic with reductions in LVEF to <50% detected at the final study visit (month 36), 12 months after completing therapy. These two patients received cumulative MITO doses of 72 and 40 mg/m2. Both of these patients remain asymptomatic, and repeat tests of LVEF have not been obtained. No placebo recipient in the MIMS study experienced LVEF of <50%. However, test results of LVEF for 14 of 64 (22%) placebo recipients who completed two or more annual echocardiograms varied randomly by >10% from the baseline LVEF.

Multicenter French consortium open-label study.

Eight hundred two patients in the French consortium were treated with a 20-mg/infusion of MITO in one of three ways: 1) 695 patients received monthly infusions for 6 months, 2) 178 patients received monthly infusions for 6 months followed by one or more infusions every 3 days/month, and 3) 107 received infusions every third month. The mean cumulative dose of MITO for patients in this study was 70 mg/m2, and the mean duration of follow-up was 29 months. For this cohort, there were 287 men and 515 women with mean age 38.8 years (range 14 to 72 years). EDSS scores are not available. None of these patients experienced clinically significant cardiac dysfunction. LVEF was tested at baseline and during follow-up in 656 of the 802 patients. One of the 656 patients had an LVEF of 49% at baseline. This patient was excluded from the analysis of the incidence proportion of patients developing LVEF of <50% after initiating therapy. Of the remaining 655 patients who had LVEF tested at baseline and at follow-up, 13 had asymptomatic LVEF of <50%: 5 at their most recent clinical assessment, 5 transiently with return to LVEF >50%, and 3 with LVEF <50% on two or more tests that persisted to their last visit. In all patients, therapy was discontinued when LFEV fell below 50%. All 13 patients remain in clinical follow-up and have remained asymptomatic for 4.5 to 7.0 years after initiating MITO therapy.

German retrospective study.

The 452 patients in this study received one or more infusions of 12 mg/m2 MITO every third month to a mean cumulative dose of 44 mg/m2. Mean duration of follow-up was 48 months. For this cohort, there were 178 men and 374 women with mean age 37.2 years (range 15 to 72 years). EDSS scores are not available. Two patients died of clinically significant cardiac dysfunction. The first patient, a 39-year-old man with PPMS, was treated with 12 mg/m2 MITO every third month from May 1990 to April 1992 (cumulative dose 91 mg/m2). After being denied additional MITO therapy for perceived worsening cardiac function, the patient sought and received from another physician a second course of 12 mg/m2 MITO every third month from January 1994 to February 1996 (cumulative dose 71 mg/m2). The second physician was unaware of the first course of therapy. This patient died in cardiogenic shock 3 months after completing the second course of MITO (total cumulative dose 162 mg/m2). LVEF testing and a postmortem examination were not done.

The second patient who died of cardiac dysfunction was a 65-year-old woman. She was treated with a single dose of 9 mg/m2 MITO in October 1994. Her LVEF measured by echocardiogram was >50% in November 1995. The patient died of CHF on December 8, 1998. A postmortem examination was not done.

In aggregate, 2 of 1,378 patients who participated in studies of single-agent MITO therapy for MS had CHF (incidence proportion = 0.15%, 95% CI = 0.02 to 0.52%). The relationship between MITO therapy and death of the 39-year-old patient due to cardiogenic shock is probable. The relationship between MITO therapy and CHF and death of the second patient is uncertain.

As shown in the figure, 17 (4 in the MIMS study and 13 in the French study) of the 779 patients for whom follow-up LVEF testing was done had asymptomatic LVEF of <50% (incidence proportion = 2.18%, 95% CI = 1.28 to 3.47%).8,9⇓ Duration of follow-up was a median of 29 months; 18% were followed <1 year, 65% 1 to 4 years, and 17% >4 years.

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Figure. Patients with asymptomatic left ventricular ejection fraction (LVEF) of <50% by cumulative dose. Of the 779 patients who completed baseline and follow-up LVEF testing, 17 (2.2%) experienced asymptomatic reduction of LVEF to <50%. The numbers below each column represent the number of patients included in each dose group. The incidence proportion of asymptomatic LVEF by cumulative dose is provided in parentheses.

Analyses of potential relationship between asymptomatic LVEF <50%, cumulative dose, initiating monthly versus 3-monthly dosing, duration of therapy, age, and gender.

To assess the influence of cumulative dose, initiating monthly versus 3-monthly dosing, duration of therapy, age, and gender on the incidence of asymptomatic LVEF of <50%, a stepwise logistic regression analysis was performed. This analysis did not show that any of the five factors was predictive of incidence of asymptomatic LVEF of <50% (no p < 0.25). An additional logistic regression model was fit to examine the univariate relationship between cumulative dose and incidence of asymptomatic LVEF of <50%. No significant relationship between cumulative dose and incidence of asymptomatic LVEF of <50% was found in this analysis (p = 0.2652) (odds ratio = 1.01, 95% CI = 0.992 to 1.027).

An additional analysis was performed to examine the incidence proportions of asymptomatic LVEF of <50% for cumulative doses of <100 mg/m2 and ≥100 mg/m2. This cutoff was chosen because it coincides with Novantrone package insert guidelines for obtaining repeat tests of LVEF in MS patients receiving MITO. Patients who reach cumulative dose below 100 mg/m2 strongly trend (p = 0.06) to a lower incidence (1.8%) of asymptomatic LVEF of <50% than patients at or above 100 mg/m2 (5.0%).

Discussion.

Anthracyclines and anthracenediones are often used as therapies for acute myelogenous leukemias, Hodgkin’s disease, breast cancer, and prostate cancer. The frequency of cardiac toxicity in cancer patients receiving MITO, either as a single agent or in combination with other cytotoxic agents or radiation therapy to the chest or both, was reported in five large retrospective studies. In the first study, 4,450 patients were treated with combination MITO therapy.4 Of these patients, 235 (0.2%) experienced cardiac events, including 60 cases of CHF and 103 cases of asymptomatic LVEF of <40% or LVEF that decreased by ≥10% from baseline. In the second study, 801 patients were treated with MITO combination therapy in 1 of 14 Phase 2 Southwest Oncology Group protocols.13 Of 801 patients in these protocols, 12 experienced asymptomatic LVEF reductions of ≥10% from baseline LVEF and 12 additional patients developed CHF. Risk factors for cardiotoxicity included MITO cumulative dose and dose of previous doxyrubicin therapy. In the third study, 3,200 patients were treated with MITO combination therapy.1 Of 86 patients who experienced cardiac dysfunction, all but 5 previously received doxorubicin or irradiation therapy or had underlying cardiovascular disease. Two of the remaining five patients developed CHF after cumulative MITO doses of >240 mg/m2, and three presented with decreased LVEF after cumulative doses of 60, 72, and 218 mg/m2. In the fourth study, 633 patients were treated with MITO combination therapy at doses ranging from 3 to 155 mg/m2.3 Seven patients (1.1%) experienced cardiac adverse events. One patient previously treated with MITO died of acute myocardial infarction after receiving a single 3-mg/m2 MITO dose. The remaining six patients previously were treated with doxorubicin (450 to 710 mg/m2). Four of the six patients developed CHF, and two developed decreased ejection fractions but did not develop CHF. In the fifth study, 136 young adult patients with Hodgkin’s disease were treated with various anthracyclines including MITO. Young patients are generally considered to be at low risk of cardiovascular disease because of their age.14 Patients received at least six cycles of doxorubicin, epirubicin, or MITO in combination with other cytotoxic agents. Patients with chest radiation were excluded from the analysis. The median MITO dose was 125 mg/m2 (range 70 to 165 mg/m2) for the 40 patients treated with MITO combination therapy, and the median time between end of treatment and evaluation was 65 months. Three patients treated with MITO developed CHF. Two of these patients improved with short-term therapy for CHF, and one continued to receive therapy for CHF for 3 years. Unlike results of the other studies, cardiac abnormalities in this study did not correlate with the amount of MITO administered.

The risk of cardiac toxicity during and after single-agent MITO treatment for MS has never been rigorously examined. This is an important gap in the available information about this recently approved disease-modifying therapy for worsening RRMS, SPMS, and PRMS. For this reason, we reviewed medical records of all MITO recipients in the Phase 3 trial of MITO in MS8 and of patients in two large retrospective open-label studies.9,15⇓ Patients enrolled in these studies had worsening RRMS, SPMS, or PPMS and received a wide range of cumulative doses of MITO in monthly or 3-month treatment protocols. Duration of follow-up for these patients was an average of 30 months after initiation of therapy. The mean cumulative MITO dose for participants in the three studies combined was 60.5 mg/m2; the median MITO dose was 62.5 mg/m2. Eleven percent of MITO recipients received a cumulative dose that exceeded 100 mg/m2. Within the dose ranges and duration of therapy described in these studies, 17 (<2.2%) of 779 patients who completed baseline and follow-up LVEF testing had reduction of LVEF to <50%. For these patients, none of whom experienced symptoms of CHF, logistic regression modeling failed to demonstrate a relationship between asymptomatic LVEF of <50%, duration of therapy, initiating monthly versus 3-monthly dosing, age, and gender. However, a categorical analysis indicated a strong trend (p = 0.06) between asymptomatic LVEF of <50% and cumulative dose of ≥100 mg/m2. Longer follow-up will be needed to determine if any of these patients with asymptomatic LVEF of <50% develop symptoms of CHF. Of 1,378 MITO recipients who participated in these studies, 2 (<0.2%) died of CHF. The death of the patient who received a cumulative dose of 162 mg/m2 was potentially preventable and underscores the following warnings contained in the package insert for Novantrone: 1) Patients should not ordinarily be treated with a cumulative dose of MITO in excess of 140 mg/m2 and 2) patients’ LVEF should be measured before each dose after they have received a cumulative dose of 100 mg/m2. We also believe patients should be explicitly asked if they previously have received MITO therapy or been exposed to other anthracyclines.

It is important to recognize certain limitations of our retrospective study. First, although the incidence proportion (2 of 1,378) of patients with CHF is accurate for all MITO recipients in these studies, follow-up LVEF testing was done in only 779 (57%) of the 1,378 patients. Thus, the incidence proportion for asymptomatic LVEF of <50% can be ascertained only for just more than half of MITO recipients in these studies. Second, available data do not permit a rigorous examination of the incidence of CHF in patients who receive higher cumulative doses of MITO or those with prolonged follow-up. Third, although we observed no significant difference in the incidence of asymptomatic LVEF of <50% in patients who initiated monthly and 3-monthly MITO therapy (p = 0.3919), our study is inherently underpowered to provide a meaningful comparison of the incidence of CHF for the monthly versus 3-month treatment protocols. However, none of these limitations, alone or in combination, invalidates the results of our study.

Although there was a low incidence of symptomatic cardiac dysfunction and asymptomatic reduction of LVEF to <50% in the MS studies we reviewed, there remains a pressing need to know the long-term safety of MITO when used as disease-modifying therapy. These data are being collected from the ongoing French study9 and in a registry (Registry to Evaluate MITO [Novantrone] Effects in Worsening MS, or RENEW).16 These ongoing studies will provide complementary data. The French study includes 695 patients who are receiving treatment with 20 mg IV of MITO every month for 6 months and 107 patients who are receiving treatment with 20 mg IV of MITO every 3 months to a maximum cumulative dose of 140 mg/m2. Of these 802 patients, 655 (82%) will have LVEF evaluated at baseline and at follow-up. The RENEW cohort will include 500 patients who will be followed up for 5 years after initiating treatment with 12 mg/m2 IV MITO every 3 months until a cumulative dose of 140 mg/m2 is reached.16 All patients in the RENEW study will have LVEF measured at baseline and before each dose after they receive a cumulative dose of 100 mg/m2. These studies will provide an opportunity to examine how reliably asymptomatic LVEF of <50% predicts symptomatic cardiac dysfunction.

Guidance for the use of MITO in patients with MS is contained in the package insert for Novantrone. This documentation indicates tests of LVEF should be obtained prior to initiating therapy, whenever there are symptoms of CHF, and prior to every infusion after reaching a cumulative dose of 100 mg/m2. Further, treatment should not ordinarily be initiated or continued in patients with LVEF of <50% or CHF or patients with clinically significant reduction in LVEF. We believe these guidelines are appropriate. However, physicians should be aware that test–retest reproducibility for echocardiograms and radionuclide angiography may vary considerably under different testing conditions and between different testing sites. For this reason, we believe it is essential to know the results of LVEF test–retest reproducibility to confidently exclude testing variability when attributing LVEF of <50% or clinically significant change in LVEF to cardiac dysfunction.

Acknowledgments

Supported by Immunex Corp. Drs. Edan, Mauch, and Hartung have received grants from or served as consultants to Immunex and other companies that make products for use in patients with MS.

Acknowledgment

The authors thank Orysia V. Lutz for editorial assistance.

Footnotes

  • Drs. Butine and Goodkin are employees of Immunex Corp., a pharmaceutical company that markets mitoxantrone in the United States. Dr. Ghalie was a full-time employee of Immunex Corp. at the time data were collected for this article.

  • Received June 29, 2001.
  • Accepted June 11, 2002.

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