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

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 Patients were withdrawn from treatment if, at any time, LVEF decreased to 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.

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.

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.

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.