Nonspecific immunosuppression did not reduce progression in patients with multiple sclerosis
ACP J Club. 1991 July-Aug;115:11. doi:10.7326/ACPJC-1991-115-1-011
The Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet. 1991 Feb 23;337:441-46.
To determine whether patients with progressive multiple sclerosis benefit from nonspecific immunosuppression therapy using cyclophosphamide and plasma exchange.
Randomized, single-blinded, controlled trial, with stratification by center and expanded disability status scale (EDSS) score.
Multiple sclerosis clinics in 9 university hospitals.
168 patients ≥ 15 years old with clinically or laboratory-supported definite, progressive-phase (chronic or relapsing) multiple sclerosis and an EDSS score between 4.0 and 6.5 were eligible. Exclusion criteria included previous treatment with immunosuppressants and serious medical illness or cognitive impairment.
No patients were lost to follow-up
Patients were allocated to receive 1 of 3 treatments: intravenous cyclophosphamide, 1 g every 2 days, to a maximum of 9 g, with oral prednisone, 40 mg for 10 days, then tapered and withdrawn on day 16 (n = 55); oral cyclophosphamide, 1.5 to 2.0 mg/kg daily for 22 weeks, with oral prednisone, 20 mg every other day tapered over 22 weeks, and plasma exchange weekly for 20 weeks (n = 57); or oral cyclophosphamide placebo daily, prednisone placebo every other day, and sham plasma exchange weekly, all for 22 weeks (n = 56). Patients were assessed every 6 months by 1 blinded and 1 nonblinded neurologist.
Main outcome measure
Treatment failure, defined as an increase in EDSS score of ≥ 1.0 point.
There were no significant differences among the treatment groups in the cumulative treatment failure rates over time (19 [35%] with cyclophosphamide, 18 [32%] with plasma exchange, 16 [29%] with placebo) in the mean time to treatment failure (24.8 mo for cyclophosphamide, 29.3 mo for plasma exchange 20.6 mo for placebo, P = 0.78 for cyclophosphamide compared with placebo, P = 0.26 for plasma exhange compared with placebo), in the number of patients who deteriorated, or in the amount of clinical deterioration seen. In the cyclophosphamide, plasma exchange, and placebo groups the proportions of women with amenorrhea were 42%, 77%, and 11%, respectively, and the proportions of patients with severe alopecia were 100% (in all who received cyclophosphamide > 2 g intravenously), 51%, and 16%, respectively.
Neither approach to nonspecific immunosuppression (intravenous cyclophosphamide with prednisone, or oral cyclophosphamide with prednisone and plasma exchange) proved beneficial in the treatment of progressive multiple sclerosis. Both treatments were associated with serious side effects.
Sources of funding: Medical Research Council of Canada; Bristol Myers Pharmaceutical Group (cyclophosphamide); Upjohn Company of Canada (prednisone).
Address for article reprint: Dr. J.H. Noseworthy, Department of Neurology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA.
This study showed that patients with progressive multiple sclerosis who receive nonspecific immunosuppression therapy derive no substantial benefit. The multicenter design upheld high standards of rigor. The investigators planned the study to have a 90% chance (power) to detect a 30% difference in the failure rates between one of the active treatment groups and the control group, so that benefit is unlikely to have been missed.
Despite the impressive design, this study remains preliminary. First, the main outcome measure may have been insensitive to subtle but important benefits of therapy. Second, the patients on placebo received supplemental steroids (prescribed by the unblinded neurologist) more often and earlier than did the patients on active treatment, which may have diminished differences between groups. This suggests that the active-treatment interventions were perceived by the unblinded neurologists as more effective. Third, a recent, randomized, single-blind trial, reported only in abstract form, appears to provide evidence for the effectiveness of intravenous cyclophosphamide-ACTH and suggests that maintenance therapy provides benefit for up to 30 months (1). In short, the Canadian Cooperative Trial does not end the controversy about therapy with cyclophosphamide for multiple sclerosis.
John R. Absher, MD
UCLA School of MedicineLos Angeles, California, USA
1. Mackin GA, Weiner HL, Orav JA, et al. IV cyclophosphamide/ACTH plus maintenance cyclophosphamide boosters in progressive MS: final report of the Northeast Cooperative MS Treatment Group I. Neurology. 1991;41(Suppl 1):147.
The proportion of patients stabilized or improved in the study by Mackin and colleagues was less than in the placebo limb of the Canadian trial, and it appears unlikely that more aggressive regimens with cyclophosphamide will help patients with progressive multiple sclerosis.
John H. Noseworthy, MD