Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial
Hartung H-P, Gonsette R, König N, Kwiecinski H, Guseo A, Morrissey SP, et al. ;
Commented by , 24 Feb 2003
Background
Disease modifying treatment of multiple sclerosis (MS) has been approved for patients with relapsing remitting disease (RRMS). Three therapies are currently used: Interferon beta -1 b, interferon beta-1 a and glatiramer acetate.
Clinical trails have been conducted in patients with secondary progressive MS (SPMS), but only one study using interferon beta -1 b, showed lengthened time to onset of sustained progression of disability.
In this regard there has been a search for other potential immuno-suppressants and there was a rationale to test mitoxantrone, which is an anthrecenedione normally used to treat various malignant disorders.
Aim
To test if mitoxantrone recipients experience significantly less progression of disability and fewer relapses than placebo recipients in patients with MS.
Methods
194 patients with worsening RRMS or SPMS were randomly assigned treatment with placebo, mitoxantrone 5 mg/m2 (exploratory dose comparison), or mitoxantrone 12 mg/m2 (primary efficacy assessment) administered intravenously every 3 months for 24 months.
The primary endpoint was a multivariate analysis of five clinical measures. A subset of 110 patients underwent unenhanced and gadolinium enhanced MRI of the brain annually. Cardiac monitoring was carried out before treatment and then once a year.
Results
188 patients were assessed after 24 months. A significant treatment effect (p<0,0001) was detected for the primary outcome. The univariate analysis of the five components of the composite outcome also showed significant treatment effects for
- change in EDSS (p=0.0194)
- change in ambulation index (p=0.0306)
- number of relapses treated with glucocorticosteroids (p=0.0002)
- time to first relapse (p=0.0004)
- change in standardized neurological status (p=0.0268)
MRI data showed significantly fewer patients with enhancing lesions (p=0,02) and less increase in the number of T2-weighted lesions (p=0.02) in the mitoxantrone group.
No serious adverse events were recorded, although a decrease in left-ventricular ejection fraction (< 50%) was more frequent in patients receiving< SPAN lang= EN-US> mitoxantrone than placebo (two patients in the 5 mg/m2 group and two patients in the 12 mg/m2 group).
Discussion
The study show convincing treatment effect of mitoxantrone on clinical endpoints and the drug is considered to be an effective and well tolerated treatment for patients with worsening RRMS and SPMS.
A drawback of the therapy is the potential cardiotoxicity of the drug, since congestive heart failure has been reported in 2,6-6,0% of patients who received cumulative doses of mitoxantrone up to 140 mg/m2.
Still, nearly all mitoxantrone recipients who had cardiac dysfunction in these studies, had preexisting cardiovascular disease, or had received additional cardiotoxic treatment according to the authors. It is clear that further information will be needed to enlighten this issue, and caution is recommended when a cumulative dose of 100 mg/m2 is reached.
The study provides encouraging documentation for a new therapeutic option in SPMS. If future studies should confirm serious cardiotoxiticy due to a high cumulative dose, the drug will still be recommended for treatment of patients with aggressive disease course in a limited time interval.