Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis : A comparative study
Perini P, Calabrese M, Tiberio M, Ranzato F, Battistin L, Gallo P;
Commented by , 23 May 2006
Mitoxantrone (Mito) is the most efficacious treatment for secondary progressive MS (SPMS), although long term use is limited by serious adverse effects such as cardiac failure and risk of leukemia. In the search for alternative treatment options, older immunosuppressants such as Azathioprine and Cyclophosphamide (Cy) have been examined, and promising results have been obtained using high-dose therapy in the early course of aggressive MS. Still, efficacy of these drugs has never been compared with Mito.
To compare the clinical efficacy and safety profile of Mito and Cy.
The authors used 50 patients with SPMS who had sustained progression (loss of ≥ <>>1 EDSS point over the prior 2 years and ≥ 1 relapse over the last year). Twenty-five patients were treated with Mito and twenty-five with Cy in an open label study design.
Cy was given I.V. every month for the first year and every second month for the second year. The dose of Cy started at 600 mg/m² and increased by 200 mg/m² every month depending on the lymphocyte counts. Urine-bladder condition was monitored throughout the study.
Mito dosage was 8 mg/m² administered I.V. every second month for two years. Cardiac function was measured twice during the study. All patients underwent MRI at study entry as well as after 2 and 3 years.
The two drugs exerted a non-distinguishable significant effect on clinical and radiological measurements.
Reductions in relapse rate (Mito -88%; p=0.001, Cy -86%; p=0.003) and disability progression (Mito -0.9 EDSS; p=0.01, Cy -0.9 EDSS; p=0.01) were equal.
A subgroup of therapy responders were characterized by shorter duration of the secondary progressive phase (Mito 14; Cy 17) and had significant improvement of EDSS by the end of therapy (Mito; p<0.0001, Cy; p=0.004).
Safety profiles of both drugs were acceptable.
Cy therapy was significantly less expensive.
Dr Blinkenberg's comments
This is the first trial comparing efficacy of Mito with another cytotoxic agent, in this case Cy. The impact on disease activity and progression of both drugs are remarkably good and similar, and the safety profile is acceptable, although there is an overweight of side effects in the Cy group. The study design is open label, which hampers the strength of evidence evaluation.
An optimistic conclusion of the study is that Cy seems to be an efficacious treatment in early aggressive SPMS, and might therefore replace Mito therapy before cardiac symptoms evolve. A considerable part of SPMS patients receiving Mito treatment are currently close to the maximum cumulative dose of 140 mg/m². These patients need an equally efficacious therapy or have to face increasing disease activity and disability.
There are still no results on the safety hazards of shifting high-dose cytotoxic treatment in a long-term perspective, and a thorough evaluation of risk-benefit would need to be considered in each case until relevant data are available.
The authors suggest that Cy should be considered as a first line rescue therapy for non responding RRMS and rapidly deteriorating SPMS patients, although randomized controlled trials have not been conducted yet. Unfortunately, time seem to be running out for some of our MS patients in the wait for such documentation.