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

Richard K. Burt, Roumen Balabanov, Joachim Burman, Basil Sharrack, John A. Snowden, Maria Carolina Oliveira, Jan Fagius, John Rose, Flavia Nelson, Amilton Antunes Barreira, Kristina Carlson, Xiaoqiang Han, Daniela Moraes, Amy Morgan, Kathleen Quigley, Kimberly Yaung, Regan Buckley, Carri Alldredge, Allison Clendenan, Michelle A. CalvarioJacquelyn Henry, Borko Jovanovic, Irene B. Helenowski

Research output: Contribution to journalArticlepeer-review

178 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)165-174
Number of pages10
JournalJAMA - Journal of the American Medical Association
Issue number2
StatePublished - Jan 15 2019

Bibliographical note

Funding Information:
by financial support from the Danhakl family, the Cumming Foundation, the McNamara Purcell Foundation, Morgan Stanley, and the National Institute for Health Research Sheffield Clinical Research Facility. There was no industry support or pharmaceutical support for the study.

Funding Information:
completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Balabanov reported receipt of personal fees from Biogen and Sanofi Genzyme and grants from Biogen. Dr Burman reported receipt of grants from the Swedish Society for Medical Research and the Swedish Society for Medicine. Dr Snowden reported receipt of speaking honoraria from Sanofi and Jazz. Dr Fagius reported receipt of personal fees from Sanofi OY, Biogen, and Novartis. Dr Rose reported receipt of grants from the National Multiple Sclerosis Society, the Guthy Jackson Foundation, Biogen, and Teva Neuroscience. Dr Nelson reported receipt of grants from Alkermes, Novartis, Biogen, Genentech, Sanofi Genzyme, and the National Multiple Sclerosis Society; receipt of speakers bureau fees from Genentech, Sanofi Genzyme, Acorda, and the Consortium of Multiple Sclerosis Centers; advisory board membership for Sanofi Genzyme; and chairing a review panel for an MS research program for the US Department of Defense. No other disclosures were reported.

Publisher Copyright:
© 2019 American Medical Association. All rights reserved.


  • Adolescent
  • Adult
  • Antilymphocyte Serum/therapeutic use
  • Combined Modality Therapy
  • Cyclophosphamide/therapeutic use
  • Disease Progression
  • Female
  • Hematopoietic Stem Cell Transplantation/adverse effects
  • Humans
  • Immunologic Factors/therapeutic use
  • Immunosuppressive Agents/therapeutic use
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting/drug therapy
  • Young Adult

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Randomized Controlled Trial
  • Multicenter Study
  • Journal Article
  • Comparative Study


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