title: High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report.
abstract: OBJECTIVE
  Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.
  
  
  OBJECTIVE
  To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT.
  
  
  METHODS
  Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.
  
  
  METHODS
  Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.
  
  
  METHODS
  The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.
  
  
  RESULTS
  Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.
  
  
  CONCLUSIONS
  At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.
authors.affiliation: Colorado Blood Cancer Institute, Denver.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Nash
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas.
authors.forename: George J
authors.initials: GJ
authors.lastname: Hutton
authors.affiliation: Department of Neurology and Neuroscience, The Ohio State University, Columbus.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.affiliation: Division of Cancer Medicine, Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Uday
authors.initials: U
authors.lastname: Popat
authors.affiliation: Blood and Marrow Transplant Program, Division of Hematology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.affiliation: Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Griffith
authors.affiliation: Department of Medicine, Division of Brain Sciences, Imperial College London, London, England.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Muraro
authors.affiliation: Department of Neurology, City of Hope National Medical Center, Duarte, California.
authors.forename: Harry
authors.initials: H
authors.lastname: Openshaw
authors.affiliation: Hematology and Blood and Marrow Transplant, University of California, San Francisco, Medical Center, San Francisco10Clinical Trials Group, Immune Tolerance Network, San Francisco, California.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sayre
authors.affiliation: Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas12Neurology Section, Veterans Affairs North Texas Health Care System, Dallas13associate editor, JAMA Neurology.
authors.forename: Olaf
authors.initials: O
authors.lastname: Stüve
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada15NeuroRx, Montreal, Quebec, Canada.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Arnold
authors.affiliation: Rho Inc, Chapel Hill, North Carolina.
authors.forename: Meagan E
authors.initials: ME
authors.lastname: Spychala
authors.affiliation: Rho Inc, Chapel Hill, North Carolina.
authors.forename: Kaitlyn C
authors.initials: KC
authors.lastname: McConville
authors.affiliation: Biomarker and Discovery Research, Immune Tolerance Network, San Francisco, California.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Harris
authors.affiliation: Biomarker and Discovery Research, Immune Tolerance Network, San Francisco, California.
authors.forename: Deborah
authors.initials: D
authors.lastname: Phippard
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington19Medical Oncology Division, University of Washington Medical Center, Seattle.
authors.forename: George E
authors.initials: GE
authors.lastname: Georges
authors.affiliation: Department of Neurology, University of Washington Medical Center, Seattle.
authors.forename: Annette
authors.initials: A
authors.lastname: Wundes
authors.affiliation: Department of Rehabilitation Medicine, University of Washington, Seattle.
authors.forename: George H
authors.initials: GH
authors.lastname: Kraft
authors.affiliation: Swedish Neuroscience Institute, Seattle, Washington.
authors.forename: James D
authors.initials: JD
authors.lastname: Bowen
mesh_terms: D000328:Adult; D003131:Combined Modality Therapy; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy / Q000601:surgery; D014182:Transplantation, Autologous / Q000009:adverse effects / Q000379:methods; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents