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Survival, and time to an advanced disease state or progression, of untreated patients with moderately severe multiple sclerosis in a multicenter observational database: relevance for design of a clinical trial for high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation

Sylvia Lawry Centre for Multiple Sclerosis Research, Munich, Germany, daumer{at}slcmsr.org

L M Griffith

Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

W Meister

Sylvia Lawry Centre for Multiple Sclerosis Research, Munich, Germany

R A Nash

Clinical Research Division, Fred Hutchinson Cancer Research Center, and University of Washington, Seattle, WA, USA

J S Wolinsky

Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX, USA

Despite prolonged survival, patients with multiple sclerosis (MS) experience considerable morbidity, which adversely impacts quality of life. To assess the risk-benefit of a clinical trial of high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation for MS, we sought to determine the natural history of the disease in a comparison group of untreated patients. We identified 285 individuals with 2132 combined observation years (median: 5.6 years; 5th to 95th percentile: 1-21 years), with Expanded Disability Status Scale (EDSS) scores of 3.0-5.5 at baseline observation. Disease-related mortality was zero at five years, 5.4% at 10 years, and 22% at 15 years (40 patients contributing to the data point; 95% confidence interval: 4-32%). Risk for progression to advanced disability, defined as an EDSS score of 8, was very low for the subgroup with a baseline EDSS score of 3-3.5; however, for those with a baseline EDSS score of 4-5.5, 3% had advanced disability after two years, 5% after three years, 6% after four years, 12% after five years, and 40% after 10 years. The estimated probability of disease progression, defined as an increase in EDSS score by 1.0 sustained for at least 180 days, was 5% after one year, 14% after two years, 22% after three years, 38% after five years, 57% after 10 years, and-80% after 20 years of observation. The relevance of these features to the design of the clinical trial is discussed.

Key Words: autologous hematopoietic cell transplantation • immunosuppressive therapy • multiple sclerosis • survival • time-to-progression

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