Abstract
Background
Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients.
This is an update of the Cochrane review “Mitoxantrone for multiple sclerosis” (published on Cochrane Database of Systematic Reviews 2013, Issue 5).
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 (23 May 2013). We also undertook handsearching and contacted trialists and pharmaceutical companies.
Selection criteria
Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included.
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 patients 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 limited number of included subjects 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.
Authors’ conclusions
MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients 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 disfunction and therapy-related acute leukaemias, occurring in about 12% and 0.8% of MX-treated patients respectively.
MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients’ risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.
Plain language summary
The use of the immunosuppressive drug mitoxantrone (MX) in people with multiple sclerosis (MS)
This is an update of the Cochrane review “Mitoxantrone for multiple sclerosis” (published on Cochrane Database of Systematic Reviews 2013, Issue 5).
MX is considered an immune-mediated chronic disorder of the central nervous system (CNS), characterized by multiple areas of inflammation and demyelination. Several drugs such as steroids as well as immunomodulant and immunosuppressive agents have been used to treat the disease course. Among them, MX, an immunosuppressive agent widely used for treatment of breast cancer and leukaemia, has been tested in MS individuals. Two hundred seventy-five articles were identified by the search strategy up to May 2013. Three trials contributed to this review, comprising a total of 221 participants. Data show that MX was moderately effective in reducing the risk of MS progression and the frequency of relapses in short-term follow-up (up to two years) of patients affected by worsening relapsing-remitting MS (RRMS), progressive relapsing MS (PRMS) and secondary progressive MS (SPMS). However, caution must be exercised when interpreting these results because of the heterogeneous characteristics and quality of the included trials, which are different in terms of treatment schedules and types of enrolled patients.
The most frequent adverse effects were nausea and vomiting, alopecia, urinary tract infections and transitory leucopenia; 35% of MX-treated female participants developed transitory amenorrhoea, and almost 15% developed a persistent amenorrhoea which was still present at the end of the follow-up period. Data from studies with longer follow-up and out of included trials have raised concerns about cardiotoxicity and acute leukaemias, occurring in about 12% and 0.8% of MX-treated patients respectively.
For these reasons, MX treatment should be limited to patients with worsening RRMS and SPMS after a careful assessment of the individual patients’ risk and benefit profiles, also considering the present availability of alternative therapies with less severe adverse events. Moreover, MX-treated patients need to be followed-up after the end of treatment to control the risk of serious adverse events.
