Mitoxantrone is very effective DMT

Mitoxantrone is a very effective DMT. So why aren't we using it more? #MSBlog #MSResearch

Martinelli Boneschi et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013 May 31;5:CD002127.

BACKGROUND: This is an updated Cochrane review of the previous published version. Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in MSers.

OBJECTIVES: The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. 

SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies.

DATA COLLECTION AND ANALYSIS: The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used.

MAIN RESULTS: Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of MSers with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX.

Oncologists call mitoxantrone the 'Blue Devil'.

AUTHORS' CONCLUSIONS: MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in MSers affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic cardiac dysfunction (~12%) and therapy-related acute leukaemias (~0.8%), which are increasingly reported in the literature. MX should be limited to treating MSers with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual MSers' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.

"Someone recently asked about the effectiveness of mitoxantrone. This review is therefore very timely. These are impressive results and places mitoxantrone high the list on relative efficacy. It is one of the highly effective DMTs."

"Mitoxantrone is another agent that brutally exposes the therapeutic window of opportunity. If you use it early it stops and often reverses disability, but if you use it late MSers continue to progress, but at a slower rate. The slower rate of progression is a win for us, but if you have MS it is an unimpressive outcome. We have previously addressed this issue in a survey on our blog; MSers with progressive disease want to stabilise their disease or improve."

"Mitoxantrone is not without side effects. It is all about risk and benefits. The cardiotoxicity is dose limiting therefore you can only receive the drug for a maximum of 2 years. What happens after the 2 years? In some centres it is used as an induction agent and the mitoxantrone is followed up with either interferon-beta or glatiramer acetate. The main risks relate to its effect in woman on fertility; this is age related and the risk of delayed treatment-related leukaemia. The latter is a very characteristic leukemia and has a genetic finger print that is characteristic of mitoxantrone. The type of leukemia is called promyelocytic leukemia and is associated with a 50% mortality. In other words 50% of individuals who get this leukemia die from it. I most point out that this complication is dose related so the more mitoxantrone you receive the greater your chances. It is interesting that mitoxantrone has a license for the treatment of MS in many countries despite these risks. So why then did the regulators say no to oral cladribine? Some food for thought."

Multiple Sclerosis Research: Survey results: neuroprotection - 27 Apr 2012. Survey results: neuroprotection ... Neuroprotection in progressive MS in unlikely to result in recovery of function as progressive MSers have usually exhausted the nervous system's ability to recover.......