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Preliminary Communication
January 15, 2019

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial

Author Affiliations
  • 1Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 3Neurology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
  • 4Department of Neuroscience and Sheffield NIHR Translational Neuroscience BRC, Sheffield Teaching Hospitals NHS Foundation Trust & University of Sheffield, Sheffield, England
  • 5Departments of Haematology and Oncology and Metabolism, Sheffield Teaching Hospitals NHS Foundation Trust & University of Sheffield, Sheffield, England
  • 6Center for Cell-Based Therapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
  • 7Department of Neurology, University of Utah, Salt Lake City
  • 8Division of Multiple Sclerosis, Department of Neurology, University of Minnesota, Minneapolis
  • 9Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
  • 10Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  • 11Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
JAMA. 2019;321(2):165-174. doi:10.1001/jama.2018.18743
Visual Abstract.
Visual Abstract.
Nonmyeloablative Hematopoietic Stem Cell Transplantation and Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis
Nonmyeloablative Hematopoietic Stem Cell Transplantation and Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis
Key Points

Question  Is nonmyeloablative autologous hematopoietic stem cell transplantation (HSCT) more effective than disease-modifying therapy for patients with highly active relapsing-remitting multiple sclerosis (MS)?

Findings  In this randomized clinical trial that included 110 patients with relapsing-remitting MS, treatment with nonmyeloablative HSCT compared with disease-modifying therapy resulted in a significantly prolonged time to disease progression (hazard ratio, 0.07).

Meaning  In this preliminary study, nonmyeloablative HSCT was more effective than disease-modifying therapy for patients with relapsing-remitting MS.

Abstract

Importance  Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

Objective  To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

Design, Setting, and Participants  Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

Interventions  Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

Main Outcomes and Measures  The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios.

Results  Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, −1.7; 95% CI, −2.03 to −1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

Conclusions and Relevance  In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

Trial Registration  ClinicalTrials.gov Identifier: NCT00273364

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