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

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• 作者：Dr Harold L Atkins ; MD^a ; ^b ; ^c ; ^{hatkins@ohri.ca" class="auth_mail" title="E-mail the corresponding author} ; Marjorie Bowman ; MScN^a ; ^e ; David Allan ; MD^a ; ^b ; ^c ; Grizel Anstee ; MD^b ; Prof Douglas L Arnold ; MD^f ; ^h ; Prof Amit Bar-Or ; MD^f ; ^g ; Isabelle Bence-Bruckler ; MD^b ; ^c ; Paul Birch ; MLTⁱ ; Prof Christopher Bredeson ; MD^a ; ^b ; ^c ; Jacqueline Chen ; PhD^f ; ^j ; Prof Dean Fergusson ; PhD^a ; ^c ; Mike Halpenny ; MLTⁱ ; Linda Hamelin ; RN^b ; Prof Lothar Huebsch ; MD^b ; ^c ; Brian Hutton ; PhD^a ; Pierre Laneuville ; MD^k ; ^l ; Yves Lapierre ; MD^f ; Hyunwoo Lee ; BSc^f ; Lisa Martin ; MLTⁱ ; Sheryl McDiarmid ; RN^b ; Prof Paul O'Connor ; MD^m ; Timothy Ramsay ; PhD^a ; ^c ; Mitchell Sabloff ; MD^b ; ^c ; Lisa Walker ; PhD^d ; ^e ; Prof Mark S Freedman ; MD^a ; ^c ; ^e
• 刊名：The Lancet
• 出版年：2016
• 出版时间：6-12 August 2016
• 年：2016
• 卷：388
• 期：10044
• 页码：576-585
• 全文大小：550 K

文摘

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.