Mitoxantrone in progressive multiple sclerosis: when and how to treat?
Introduction
Mitoxantrone (MX), a cytotoxic drug exhibiting very potent immunosuppressive properties, has been approved by the United States Food and Drug Administration (FDA) for the treatment of patients with progressive multiple sclerosis (MS).
According to the FDA recommendations, MX is indicated “for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary progressive (SP), progressive relapsing, or worsening relapsing–remitting (RR) MS (i.e. patients whose neurologic status is significantly abnormal between relapses)”. Based on the FDA recommendations, it has been estimated that half of 140 000 patients with severe secondary progressive MS are eligible for MX therapy in the USA [1]. This is almost as many patients as for existing therapies. This evaluation seems overestimated and the FDA indications should be refined.
Section snippets
Immunosuppressive therapies in progressive phase
Immunosuppressors have been used in progressive MS since several decades, but their efficacy on progression is still debated. Comparing the therapeutic benefit (percentage of treated patients doing better than those from the placebo group) as demonstrated by treatment failure (EDSS+≥1 confirmed at 3 months) in placebo-controlled trials, it appears that cyclosporine A [2], methotrexate [3] and azathioprine [4] do not reach a clinically significant benefit as defined by Goodkin et al. [3]: 50%
When to treat with mitoxantrone
Initially, MX has been proposed as a rescue therapy for patients with a rapidly progressing MS who fail to respond to currently available treatments [29]. The recent recommendations of the FDA are somewhat indefinite and should be refined. Given the rather limited experience with this new immunosuppressor in MS and potential long-term toxicity, MX should be reserved to two main categories of patients. A first group concerns RR patients experiencing frequent, disabling relapses likely leading to
How to treat
The treatment regimen with immunosuppressors is an important issue. Most studies with MX were performed with the intermittent administration schedule every 3 or 4 weeks used in cancer therapy. With this treatment regimen, however, administration of MX is restricted to 1 year maximum.
In preliminary studies [18], we found that MX produced a marked immunosuppression (leukopenia≤2000/ml, lymphopenia≤1000/ml) similar to that obtained with cyclophosphamide, after three or four monthly infusions and
The benefit/risk ratio
The main advantages of MX compared with CY are a better immediate tolerance (mild alopecia and gastrointestinal discomfort, no sustained myelotoxicity) and a lower long-term toxicity. In contrast with CY, MX has in theory less negative effects on reproductive organs and a weak carcigenocity.
Even though one case of amenorrhoea only was reported in cancer therapy [33], menstrual disorders are observed more frequently than expected in MS patients treated with MX. Amenorrhoea seems related to the
Conclusions
Mitoxantrone has been found effective on relapse rate and progression of disability in several open studies and in three prospective, randomized, controlled clinical trials. A recent report on disease modifying therapies in MS [54] classifies MX as “possibly” effective but the evidence of beneficial effects of MX will likely become stronger after the publication of the last phase III trial [26]. Of note that several observations have demonstrated a marked decrease in MRI activity during MX
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