Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis [RETIRED]

Abstract

Objective: The chemotherapeutic agent mitoxantrone was approved for use in multiple sclerosis (MS) in 2000. After a review of all the available evidence, the original report of the Therapeutics and Technology Assessment Subcommittee in 2003 concluded that mitoxantrone probably reduced clinical attack rates, MRI activity, and disease progression. Subsequent reports of decreased systolic function, heart failure, and leukemia prompted the US Food and Drug Administration to institute a "black box" warning in 2005. This review was undertaken to examine the available literature on the efficacy and safety of mitoxantrone use in patients with MS since the initial report.Methods: Relevant articles were obtained through a review of the medical literature and the strength of the available evidence was graded according to the American Academy of Neurology evidence classification scheme. Results:The accumulated Class III and IV evidence suggests an increased incidence of systolic dysfunction and therapy-related acute leukemia (TRAL) with mitoxantrone therapy. Systolic dysfunction occurs in ϳ12% of patients with MS treated with mitoxantrone, congestive heart failure occurs in ϳ0.4%, and leukemia occurs in ϳ0.8%. The number needed to harm is 8 for systolic dysfunction and 123 for TRAL. There is no new efficacy evidence that would change the recommendation from the previous report. Conclusions:The risk of systolic dysfunction and leukemia in patients treated with mitoxantrone is higher than suggested at the time of the previous report, although comprehensive postmarketing surveillance data are lacking. Neurology ® 2010;74:1463-1470 GLOSSARY AAN ϭ American Academy of Neurology; CHF ϭ congestive heart failure; CML ϭ chronic myeloid leukemia; FDA ϭ Food and Drug Administration; LVEF ϭ left ventricular ejection fraction; MIMS ϭ Mitoxantrone in Multiple Sclerosis Group; MS ϭ multiple sclerosis; MX ϭ mitoxantrone hydrochloride; NNH ϭ number needed to harm; RRMS ϭ relapsing-remitting multiple sclerosis; SPMS ϭ secondary-progressive multiple sclerosis; TRAL ϭ therapy-related acute leukemia; TTA ϭ Therapeutics and Technology Assessment.

Acute myeloid leukemia developing in patients with autoimmune diseases

“…The majority of cases was APL and occurred within three years of mitoxantrone treatment. 101 The previous studies and reports collectively showed a high incidence of AML in multiple sclerosis and of AML-M3 after mitoxantrone exposure. Long and close follow up for hematologic changes in multiple sclerosis patients, particularly for those exposed to cytotoxic agents, should be part of their management.…”

Therapeutic Approach to the Management of Pediatric Demyelinating Disease: Multiple Sclerosis and Acute Disseminated Encephalomyelitis

“…Mitoxantrone is approved for the treatment of worsening adult RRMS; however, given the risk of cardiotoxicity and high rates of leukemia [99], use of this therapy in pediatric MS is discouraged.…”

Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned

“…However, despite these therapeutic advances, a subset of patients seem refractory and rapidly develop severe neurological impairment, whereas other patients may have a slower progression of illness that ultimately results in marked functional disabilities. Only a single agent, mitoxantrone, has been shown to temporarily halt or slow the tempo of SP-MS [5,6], but even then, this occurs only in SP-MS patients who have highly active inflammatory events.HSCT was originally conceived as a method of rescuing patients from prolonged life-threatening bone marrow aplasia that results from the administration of high-dose total body irradiation or myeloablative chemotherapy. In the context of MS, a single administration of high-dose chemotherapy and total body irradiation (used individually or together) is meant to suppress or ablate the endogenous immune Electronic supplementary material The online version of this article…”

“…However, despite these therapeutic advances, a subset of patients seem refractory and rapidly develop severe neurological impairment, whereas other patients may have a slower progression of illness that ultimately results in marked functional disabilities. Only a single agent, mitoxantrone, has been shown to temporarily halt or slow the tempo of SP-MS [5,6], but even then, this occurs only in SP-MS patients who have highly active inflammatory events.…”