During clinical trials, treatment with mitoxantrone resulted in generally manageable side effects that were primarily mild to moderate. During the 2-year trial, the most frequent side effects reported by patients treated with 12 mg/m2 were nausea, alopecia, upper respiratory tract infection, urinary tract infection, menstrual disorder, and transient neutropenia.
Dose-related cardiotoxicity has been reported in patients receiving mitoxantrone. Reports of cardiac adverse effects and leukemia led the United States Food and Drug Administration to institute a "black box" warning in 2005. According to a 2010 report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, the risk of cardiotoxicity and leukemia in patients treated with mitoxantrone is higher than that suggested at the time of the 2003 report (19). A study suggests a significantly increased risk for cardiovascular comorbidity and toxicity in multiple sclerosis patients treated with methotrexate (24). Heart involvement is dependent on the dose and the duration of methotrexate exposure but not on age or disease duration. A retrospective observational cohort study on mitoxantrone-treated patients with multiple sclerosis with a median follow-up of 8.7 years showed an increased risk of leukemia and colorectal cancer (03).
Multiple sclerosis patients of childbearing age are at risk of developing mitoxantrone-induced amenorrhea, and this risk can be reduced by estroprogestinic treatment (08).
There are several case reports of acute myeloid leukemia as an adverse event associated with mitoxantrone treatment in multiple sclerosis (25). One patient developed acute myeloid leukemia 11 months after mitoxantrone had been discontinued but recovered completely with stabilization of the neurologic disease following treatment with chemotherapy and autologous bone marrow transplantation (04). There is one report of death in a case of childhood-onset multiple sclerosis due to acute myeloid leukemia with 11q23 MLL gene rearrangement following mitoxantrone treatment (22). Because of an increasing number of reports of acute myeloid leukemia after mitoxantrone therapy in multiple sclerosis patients, hematological monitoring is recommended for at least 5 years after the last dose of mitoxantrone. Multiple sclerosis treatment regimens, which limit the mitoxantrone dose to less than 60 mg/m2, reduce the risk of therapy-related acute leukemia (10).
Management. Cardiac assessment prior to start of therapy with mitoxantrone is recommended because reduction in cardiac high-energy phosphates in some patients with multiple sclerosis causes a subclinical involvement of the heart. It is recommended that patients receiving mitoxantrone should have cardiac monitoring because subclinical reductions in left ventricular ejection fraction may occur with serial doses. The myocardial performance index may be an adjunctive parameter to conventional echocardiography for detecting subclinical cardiotoxicity of mitoxantrone in the clinical management of multiple sclerosis patients (23). The lifetime cumulative dose should not exceed 140 mg/m2. An open-label study on patients treated with mitoxantrone showed that those receiving concomitant dexrazoxane, a cardioprotective agent, exhibited a significantly lesser decline in left ventricular ejection fraction (01).
Taking the risks into consideration, mitoxantrone is still a reasonable option for patients with relapsing-remitting or secondary progressive multiple sclerosis who are progressing despite current disease-modifying therapies. The risks of substantial myelosuppressive and cardiotoxic effects can be reduced by careful patient selection, drug administration, and monitoring. Nevertheless, it is recommended that all potential serious adverse events be carefully weighed against the potential benefits in an individual patient before starting mitoxantrone therapy.
