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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
Multiple Sclerosis Scientific Research Foundation.
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.
Harold L
HL
Atkins
Ottawa Hospital Research Institute, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.
Marjorie
M
Bowman
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.
David
D
Allan
The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada.
Grizel
G
Anstee
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; NeuroRx Research, Montreal, QC, Canada.
Douglas L
DL
Arnold
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.
Amit
A
Bar-Or
The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
Isabelle
I
Bence-Bruckler
Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.
Paul
P
Birch
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.
Christopher
C
Bredeson
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada; Department of Neurosciences, Cleveland Clinic, Cleveland, OH, USA.
Jacqueline
J
Chen
Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
Dean
D
Fergusson
Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.
Mike
M
Halpenny
The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada.
Linda
L
Hamelin
The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
Lothar
L
Huebsch
Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Brian
B
Hutton
McGill University Health Center, Montreal, QC, Canada; Division of Oncology, Department of Medicine, McGill University, Montreal, QC, Canada.
Pierre
P
Laneuville
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
Yves
Y
Lapierre
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
Hyunwoo
H
Lee
Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.
Lisa
L
Martin
The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada.
Sheryl
S
McDiarmid
Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Paul
P
O'Connor
Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
Timothy
T
Ramsay
The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
Mitchell
M
Sabloff
School of Psychology, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.
Lisa
L
Walker
Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.
Mark S
MS
Freedman
D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D002066:Busulfan / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000628:therapy*; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D055815:Young Adult
D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D002066:Busulfan