In 2000, mitoxantrone was approved by the FDA for secondary progressive, worsening relapsing-remitting, and progressive-relapsing forms of multiple sclerosis (MS). The drug’s use has been limited by concerns about potential cardiotoxicity and acute leukemia. To provide more data on its cardiotoxicity, researchers conducted this retrospective chart review of 163 patients followed at their clinic for nearly 10 years.

Median follow-up duration was slightly more than 1 year, and mean cumulative dose (59.7 mg/m²) was well below the suggested lifetime ceiling of 140 mg/m². Nonetheless, 14% of mitoxantrone-treated patients with normal baseline left ventricular ejection fractions experienced decreased ejection fractions on follow-up multiple-gated acquisition (MUGA) scans. This effect persisted in half of these patients and reversed in three patients (17%); the other six patients did not receive a follow-up MUGA study. One patient developed congestive heart failure. Sex, age, disease duration, and cumulative dose were not predictors of cardiac risk. The authors also identified other adverse effects of mitoxantrone (neutropenia, liver toxicity, and anemia).

Comment: Recently, the FDA imposed stringent guidelines for mitoxantrone use, requiring that treated patients undergo annual echocardiograms indefinitely to detect late-developing cardiac damage. Although this study showed no relation between total dose and cardiac effect, other studies involving higher mean dosages have done so. The lack of association in this study likely reflects the restricted dosing range. The cardiotoxicity reported here is greater than was seen in the phase II and III trials and in some but not all postmarketing studies. This difference is especially noteworthy considering the low cumulative doses and short follow-up. Taken together with other postmarketing work, including some studies suggesting a risk for leukemia as high as 3% with mitoxantrone (Neurology 2010; 74:1463), these finding clearly indicate that clinicians must carefully consider safety risks before prescribing mitoxantrone.

— James Stankiewicz, MD

Published in Journal Watch Neurology September 28, 2010