Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial

Harold L Atkins; Marjorie Bowman; David Allan; Grizel Anstee; Douglas L Arnold; Amit Bar-Or; Isabelle Bence-Bruckler; Paul Birch; Christopher Bredeson; Jacqueline Chen; Dean Fergusson; Mike Halpenny; Linda Hamelin; Lothar Huebsch; Brian Hutton; Pierre Laneuville; Yves Lapierre; Hyunwoo Lee; Lisa Martin; Sheryl McDiarmid; Paul O'Connor; Timothy Ramsay; Mitchell Sabloff; Lisa Walker; Mark S Freedman

doi:10.1016/S0140-6736(16)30169-6

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial

Lancet. 2016 Aug 6;388(10044):576-85. doi: 10.1016/S0140-6736(16)30169-6. Epub 2016 Jun 9.

Authors

Harold L Atkins¹, Marjorie Bowman², David Allan³, Grizel Anstee⁴, Douglas L Arnold⁵, Amit Bar-Or⁶, Isabelle Bence-Bruckler⁷, Paul Birch⁸, Christopher Bredeson³, Jacqueline Chen⁹, Dean Fergusson¹⁰, Mike Halpenny⁸, Linda Hamelin⁴, Lothar Huebsch⁷, Brian Hutton¹¹, Pierre Laneuville¹², Yves Lapierre¹³, Hyunwoo Lee¹³, Lisa Martin⁸, Sheryl McDiarmid⁴, Paul O'Connor¹⁴, Timothy Ramsay¹⁰, Mitchell Sabloff⁷, Lisa Walker¹⁵, Mark S Freedman¹⁶

Affiliations

¹ Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada. Electronic address: hatkins@ohri.ca.
² Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.
³ Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁴ The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada.
⁵ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; NeuroRx Research, Montreal, QC, Canada.
⁶ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
⁷ The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁸ Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.
⁹ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA.
¹⁰ Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
¹¹ Ottawa Hospital Research Institute, Ottawa, ON, Canada.
¹² McGill University Health Center, Montreal, QC, Canada; Division of Oncology, Department of Medicine, McGill University, Montreal, QC, Canada.
¹³ Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
¹⁴ Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
¹⁵ School of Psychology, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.
¹⁶ Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.

PMID: 27291994
DOI: 10.1016/S0140-6736(16)30169-6

Abstract

Background: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

Methods: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

Findings: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

Interpretation: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.

Funding: Multiple Sclerosis Scientific Research Foundation.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Antilymphocyte Serum / therapeutic use
Busulfan / therapeutic use
Cyclophosphamide / therapeutic use
Disease Progression
Female
Hematopoietic Stem Cell Transplantation / methods*
Humans
Immunosuppressive Agents / therapeutic use*
Magnetic Resonance Imaging
Male
Middle Aged
Multiple Sclerosis / drug therapy
Multiple Sclerosis / therapy*
Transplantation Conditioning
Transplantation, Autologous
Young Adult

Substances

Antilymphocyte Serum
Immunosuppressive Agents
Cyclophosphamide
Busulfan

Associated data

ClinicalTrials.gov/NCT01099930