Mitoxantrone is an antineoplastic agent that exerts potent immunomodulatory effects, including suppression of B cell immunity and reduction of T cell numbers. Mitoxantrone shows considerably less acute toxicity than many other anticancer drugs, the most serious side effects being irreversible cardiotoxicity (cardiomyopathy) and lymphoma. Three placebo-controlled studies were published in which the effects of this compound were investigated in MS.

A French multicentre study of 42 patients with very active disease compared treatment with either mitoxantrone (20 mg IV monthly) and methylprednisolone (1 g IV monthly), or methylprednisolone alone for six months. Blinded analysis of MRI data showed a significant and very strong suppression of disease activity in favour of the mitoxantrone-treated patients; unblended clinical assessments also favoured the mitoxantrone group.

An Italian study enrolled 51 patients with relapsing-remitting disease in a randomised, placebo-controlled design (8 mg/m2 IV monthly for one year) of two years’ duration. A trend toward reduction in disease activity as measured with clinical and MRI parameters was also found.

In a large European multicentre phase III study patients with SPMS (n =194) were randomised to either of two doses of mitoxantrone (5 mg/m2 or 12 mg/m2) or placebo, given intravenously every three months for two years. A significant beneficial effect on relapse rate and disability progression was found in the absence of severe toxicity. MRI data confirmed the beneficial effect on disease activity, although the full analysis of the MRI data has not yet been published. Treatment was well tolerated. This report convinced the FDA to license mitoxantrone for secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS.

Mitoxantrone causes mild nausea (usually without vomiting), mild alopecia, amenorrhea in up to 25 percent of premenopausal women, and dose-related bone marrow suppression. When considering treatment with mitoxantrone, it is extremely important that patients with (risk factors for) cardiac disease be excluded and that (depending on the dosage regimen used) blood counts and urine samples be taken. Echocardiographic studies should also be performed, at least every 3 months. No patient should receive an accumulative dose exceeding 100–120 mg/m2, and the drug should be discontinued if there are symptoms or clinical (or echo) findings of reduced cardiac contractility. There are a number of recent reports that mitoxantrone may induce leukaemia, presumably through its profound immunosuppressive activity.

In the opinion of the Committee, available evidence studies suggest that mitoxantrone is effective in reducing disease activity in MS. It should be considered a second-line drug to be used in patients with aggressive MS (frequent relapses with incomplete recovery) who have failed to respond adequately to the interferons or glatiramer acetate. The issue of long-term safety is likely to limit the duration of treatment.