title: Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study.
abstract: BACKGROUND
  Autologous non-myeloablative haemopoietic stem cell transplantation is a method to deliver intense immune suppression. We evaluated the safety and clinical outcome of autologous non-myeloablative haemopoietic stem cell transplantation in patients with relapsing-remitting multiple sclerosis (MS) who had not responded to treatment with interferon beta.
  
  
  METHODS
  Eligible patients had relapsing-remitting MS, attended Northwestern Memorial Hospital, and despite treatment with interferon beta had had two corticosteroid-treated relapses within the previous 12 months, or one relapse and gadolinium-enhancing lesions seen on MRI and separate from the relapse. Peripheral blood haemopoietic stem cells were mobilised with 2 g per m2 cyclophosphamide and 10 microg per kg per day filgrastim. The conditioning regimen for the haemopoietic stem cells was 200 mg per kg cyclophosphamide and either 20 mg alemtuzumab or 6 mg per kg rabbit antithymocyte globulin. Primary outcomes were progression-free survival and reversal of neurological disability at 3 years post-transplantation. We also sought to investigate the safety and tolerability of autologous non-myeloablative haemopoietic stem cell transplantation.
  
  
  RESULTS
  Between January, 2003, and February, 2005, 21 patients were treated. Engraftment of white blood cells and platelets was on median day 9 (range day 8-11) and patients were discharged from hospital on mean day 11 (range day 8-13). One patient had diarrhoea due to Clostridium difficile and two patients had dermatomal zoster. Two of the 17 patients receiving alemtuzumab developed late immune thrombocytopenic purpura that remitted with standard therapy. 17 of 21 patients (81%) improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS), and five patients (24%) relapsed but achieved remission after further immunosuppression. After a mean of 37 months (range 24-48 months), all patients were free from progression (no deterioration in EDSS score), and 16 were free of relapses. Significant improvements were noted in neurological disability, as determined by EDSS score (p<0.0001), neurological rating scale score (p=0.0001), paced auditory serial addition test (p=0.014), 25-foot walk (p<0.0001), and quality of life, as measured with the short form-36 (SF-36) questionnaire (p<0.0001).
  
  
  CONCLUSIONS
  Non-myeloablative autologous haemopoietic stem cell transplantation in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomised trial.
authors.affiliation: Division of Immunotherapy, Department of Medicine, Northwestern University, Chicago, IL 60611, USA. rburt@northwestern.edu
authors.forename: Richard K
authors.initials: RK
authors.lastname: Burt
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Loh
authors.forename: Bruce
authors.initials: B
authors.lastname: Cohen
authors.forename: Dusan
authors.initials: D
authors.lastname: Stefoski
authors.forename: Dusan
authors.initials: D
authors.lastname: Stefosky
authors.forename: Roumen
authors.initials: R
authors.lastname: Balabanov
authors.forename: George
authors.initials: G
authors.lastname: Katsamakis
authors.forename: Yu
authors.initials: Y
authors.lastname: Oyama
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Russell
authors.forename: Jessica
authors.initials: J
authors.lastname: Stern
authors.forename: Paolo
authors.initials: P
authors.lastname: Muraro
authors.forename: John
authors.initials: J
authors.lastname: Rose
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.forename: Jurate
authors.initials: J
authors.lastname: Bucha
authors.forename: Borko
authors.initials: B
authors.lastname: Jovanovic
authors.forename: Francesca
authors.initials: F
authors.lastname: Milanetti
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
authors.forename: Julio C
authors.initials: JC
authors.lastname: Voltarelli
authors.forename: William H
authors.initials: WH
authors.lastname: Burns
mesh_terms: D000328:Adult; D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D004185:Disability Evaluation; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000473:pathology / Q000628:therapy*; D011817:Rabbits; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; D003520:Cyclophosphamide