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| |  Short-Term Exposure to Cyclophosphamide Reduces Long-Term Brain Atrophy in Refractory Relapsing-Remitting Multiple Sclerosis: Presented at ECTRIMS By Chris Berrie PRAGUE, CZECH REPUBLIC -- October 22, 2007 -- Short-term exposure to the potent immunosuppressive effects of cyclophosphamide can prevent brain atrophy in patients with relapsing-remitting multiple sclerosis (RRMS) who are not responding to interferon beta (IFNbeta) or glatiramer acetate treatment, according to a comparative study presented here at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Chemotherapy, including cyclophosphamide, is an option for patients who continue to progress or to have relapses on conventional disease-modifying treatments. However, there are concerns that long-term intense immunosuppression might cause an accelerated rate of atrophy in the brain, said Jai Parumal, MD, Multiple Sclerosis Fellow, Multiple Sclerosis Clinical Research Centre, Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, in a presentation on October 13. Recent data have shown dramatic loss of brain volume in patients given short, intense immunosuppression and immunoablation. However, it remains unclear whether short-term exposure to cyclophosphamide can minimize this long-term loss of brain volume, and thus reduce the consequent clinical disability. Dr. Parumal and colleagues conducted a study of patients with confirmed RRMS who had failed therapy with IFNbeta or glatiramer acetate, defined as at least one relapse in the previous year and an accumulation of neurological disability. The 31 patients in the cyclophosphamide treatment group had a mean age of 36.4 years and 42% were male. The 41 patients in the control group had a mean age of 34.6 years and 39% were male. The control group patients had received either IFNbeta or glatiramer acetate with monthly steroids for 6 to 12 months and had declined treatment with cyclophosphamide. Both groups had RRMS confirmed by magnetic resonance imaging (MRI) at baseline. Twelve healthy volunteers were also enrolled and underwent MRI imaging to confirm the reproducibility of the imaging technique. Baseline disease characteristics across these two groups were similar for (respectively): disease duration, 8.6, 8.9 years; prior 1-year relapse rate, 2.3, 2.1; and mean expanded disability status scale (EDSS), 5.1, 4.9. Cyclophosphamide was administered at a dose of 1,000 mg/m2 IV monthly, for 6 months for almost all cases, with the cyclophosphamide dose adjusted to achieve a 2-week postcyclophosphamide white blood cell nadir of 2,000 to 2,500. Brain MRI for the treatment and nontreatment groups were (respectively): mean T2W lesion volumes, 21.8, 20.9 mL; mean T1W lesion volumes, 2.1, 2.5 mL; mean number of T1W Gd-enhancing lesions, 2.9, 2.9; patients with Gd-enhancing lesions, 76%, 71%; and mean brain volume, 1,497.5, 1,512.2 mL. No significant differences were found between these two treatment groups at baseline. Brain volumes were measured at baseline and approximately 3 years later using an identical protocol and the fully automated structural imaging evaluation using normalization of atrophy (SIENA) technique, and once compared with the baseline measures, they were expressed as percentage brain volume changes. Using SIENA, cross-sectional normalized brain volume showed a significantly greater decrease for patients not treated with cyclophosphamide over that for cyclophosphamide-treated patients (-2.7% vs -1.3%, respectively; P =.001). These changes represented annualized brain atrophy rates of 0.90 and 0.43 mL/year, respectively, despite continuous treatment with disease-modifying therapies during this period. This short-term treatment with relatively low doses of cyclophosphamide thus produced a significant reduction in brain atrophy over that of patients not treated with cyclophosphamide. Dr. Parumal stressed, "It is not only that short-term treatment with immunosuppression did not accelerate brain atrophy, which was a concern, but it turned out to be beneficial in fact, compared to patients who were not treated with [cyclophosphamide]." He indicated the need for further studies with long-term follow-up of brain atrophy in patients undergoing similar immunosuppressive treatment.
[Presentation title: Short-Term Exposure to Cyclophosphamide Is Effective in Reducing Long-Term Brain Atrophy in Refractory Relapsing-Remitting Multiple Sclerosis. Abstract P810]
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