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AAN updates 2003 recommendations regarding use of mitoxantrone for treatment of MS

Wednesday, May 12 2010 | Comments

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What's This? Based on an updated review of the literature pertaining to the use of mitoxantrone in patients with multiple sclerosis (MS), the American Academy of Neurology (AAN)'s Therapeutics and Technology Assessment (TTA) Subcommittee concluded that rates of systolic dysfunction and therapy-related acute leukemia (TRAL) appear to be higher than previously estimated.

In addition, Class I evidence to support use of the drug and comprehensive postmarketing surveillance to assess its safety are still lacking a decade after its approval for this indication.

Mitoxantrone was approved in 2000 for the treatment of aggressive relapsing-remitting MS, secondary progressive MS (SPMS), and progressive-relapsing MS based on data from the Phase III MIMS trial, a trial that the TTA group noted was considered to reflect Class II/III evidence.

In 2003, the TTA group concluded--based on a review of the available evidence--that the drug probably reduced clinical attack rates, magnetic resonance imaging (MRI)-measured disease activity, and disease progression (Level B recommendations). However, the group cautioned that the MIMS findings needed to be replicated before widespread use could be considered to determine whether the potential for cardiotoxicity and TRAL outweighed any potential benefits.

Subsequently, the TTA group noted, reports of decreased systolic function, heart failure, and leukemia with mitoxantrone prompted the Food and Drug Administration to issue a black box warning for the drug in 2005.

In the current review, the group evaluated updated evidence related to the safety and efficacy of mitoxantrone in patients with MS.

New evidence since the 2003 review included 11 studies with cardiotoxicity data and 31 studies with TRAL data, all of which were classified as Class III or IV evidence. These data suggested that systolic dysfunction occurs in approximately 12% of mitoxantrone-treated patients with MS, congestive heart failure occurs in approximately 0.4%, and leukemia occurs in approximately 0.8%.

The number needed to harm was 8 for systolic dysfunction and 123 for TRAL, although the group noted that these estimates were only approximations and were limited by differences in mitoxantrone regimens and cardiac-monitoring protocols in studies with cardiotoxicity data and differences in follow-up duration in the studies with leukemia data.

The TTA group added that the rates of TRAL and systolic dysfunction reported here appear to be low but are higher than previous estimates, with the data suggesting that these adverse effects might occur at any point after treatment initiation, even soon after the start of therapy.

The review also identified 17 new efficacy studies, but the findings as a whole did not warrant a change in the group's original recommendations regarding the drug's potential benefit. The TTA group noted that there is still no Class I evidence to support the use of mitoxantrone in MS and that the MIMS findings need to be replicated, with studies that include prospective, long-term safety analyses.

In the absence of a formal risk-benefit analysis, the group recommended that physicians treating patients with mitoxantrone adhere to the recommendations outlined in the product monograph, including those related to ejection fraction assessments, and monitor patients for TRAL with periodic complete blood cell counts.

The TTA group further advised physicians to weigh the potential benefits of treatment against the risks, while considering the availability of alternative therapies--such as interferon beta and glatiramer acetate--with less severe toxicities. (Marriott JJ, et al. Neurology 2010;74:1463-1470.)

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