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Multiple Sclerosis Unit of the Center for Neurologic Diseases, Division of Neurology, Department of Medicine (Drs. Weiner, Hafler, Mackin, and Dawson), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Biostatistics, Harvard School of Public Health (Dr. Orav), Boston, MA; Montreal Neurologic Institute (Dr. LaPierre), Montreal, PQ, Canada; Massachusetts General Hospital (Drs. Lehrich and Hauser), Boston, MA; Strong Memorial Hospital (Dr. Herndon), Rochester, NY; Geisinger Medical Center (Dr. Turel), Danville, PA; University of Minnesota Hospital (Dr. Birnbaum), Minneapolis, MN; Worcester Memorial Hospital (Dr. Fisher), Worcester, MA; Johns Hopkins Medical Center (Dr. McArthur), Baltimore, MD; Eastern Maine Medical Center (Dr. Sigsbee), Bangor, ME; Framingham Union Hospital (Dr. Safran), Framingham, MA; and Emerson Hospital and Boston University School of Medicine (Drs. Butler and Moore), Concord, MA.
Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97. In addition, patients with primary progressive MS had a poorer prognosis at 12 months than patients with secondarily progressive MS (p = 0.04). Our findings (1) support a role for immunosuppression in the treatment of MS, (2) begin to identify variables that may explain differences between studies of immunosuppression with cyclophosphamide in progressive MS, and (3) suggest that intermittent pulse therapy is an important method for the treatment of progressive MS and perhaps for earlier stages of MS as well.
Address correspondence and reprint requests to Dr. Howard L. Weiner, Center for Neurologic Diseases, Longwood Medical Research Center, 221 Longwood Avenue, Boston, MA 02115-5817
Supported by a grant from the National Multiple Sclerosis Society.
Received March 16, 1992. Accepted for publication in final form September 14, 1992.
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