title: Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial.
abstract: BACKGROUND
  Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide.
  
  
  METHODS
  In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m(2) intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with ClinicalTrials.gov, number NCT00278525.
  
  
  RESULTS
  Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04-∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted.
  
  
  CONCLUSIONS
  Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed.
  
  
  BACKGROUND
  None.
authors.affiliation: Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. rburt@northwestern.edu
authors.forename: Richard K
authors.initials: RK
authors.lastname: Burt
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.forename: Karin
authors.initials: K
authors.lastname: Dill
authors.forename: Thomas
authors.initials: T
authors.lastname: Grant
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: James
authors.initials: J
authors.lastname: Schroeder
authors.forename: Robert
authors.initials: R
authors.lastname: Craig
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hirano
authors.forename: Karin
authors.initials: K
authors.lastname: Marshall
authors.forename: Eric
authors.initials: E
authors.lastname: Ruderman
authors.forename: Borko
authors.initials: B
authors.lastname: Jovanovic
authors.forename: Francesca
authors.initials: F
authors.lastname: Milanetti
authors.forename: Sandeep
authors.initials: S
authors.lastname: Jain
authors.forename: Kristin
authors.initials: K
authors.lastname: Boyce
authors.forename: Amy
authors.initials: A
authors.lastname: Morgan
authors.forename: James
authors.initials: J
authors.lastname: Carr
authors.forename: Walter
authors.initials: W
authors.lastname: Barr
mesh_terms: D000328:Adult; D000368:Aged; D002641:Chicago; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use*; D018450:Disease Progression; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D012720:Severity of Illness Index; D012867:Skin / Q000473:pathology / Q000503:physiopathology; D057212:Therapeutic Equipoise; D014057:Tomography, X-Ray Computed; D014109:Total Lung Capacity; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014797:Vital Capacity
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide