title: Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial.
abstract: BACKGROUND
  Pretreatment with anti-thymocyte globulin (ATG) decreases the occurrence of chronic graft-versus-host disease (CGVHD) after haemopoietic cell transplantation from an unrelated donor, but evidence of patient benefit is absent. We did a study to test whether ATG provides patient benefit, particularly in reducing the need for long-term immunosuppressive treatment after transplantation.
  
  
  METHODS
  We did a phase 3, multicentre, open-label, randomised controlled trial at ten transplant centres in Canada and one in Australia. Eligible patients were aged 16 to 70 years with any haematological malignancy and a Karnofsky score of at least 60 receiving either myeloablative or non-myeloablative (or reduced intensity) conditioning preparative regimens before haemopoietic cell transplantation from an unrelated donor. We allocated patients first by simple randomisation (1:1), then by a minimisation method, to either pretransplantation rabbit ATG plus standard GVHD prophylaxis (ATG group) or standard GVHD prophylaxis alone (no ATG group). We gave a total dose of ATG of 4·5 mg/kg intravenously over 3 days (0·5 mg/kg 2 days before transplantation, 2·0 mg/kg 1 day before, and 2·0 mg/kg 1 day after). The primary endpoint was freedom from all systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Analysis was based on a modified intention-to-treat method. This trial was registered at ISRCTN, number 29899028.
  
  
  RESULTS
  Between June 9, 2010, and July 8, 2013, we recruited and assigned 203 eligible patients to treatment (101 to ATG and 102 to no ATG). 37 (37%) of 99 patients who received ATG were free from immunosuppressive treatment at 12 months compared with 16 (16%) of 97 who received no ATG (adjusted odds ratio 4·25 [95% CI 1·87-9·67]; p=0·00060. The occurrence of serious adverse events (Common Terminology Criteria grades 4 or 5) did not differ between the treatment groups (34 [34%] of 99 patients in the ATG group vs 41 [42%] of 97 in the no ATG group). Epstein-Barr virus reactivation was substantially more common in patients who received ATG (20 [one of whom died-the only death due to an adverse event]) versus those who did not receive ATG (two [no deaths]). No deaths were attributable to ATG.
  
  
  CONCLUSIONS
  ATG should be added to myeloblative and non-myeloblative preparative regimens for haemopoietic cell transplantation when using unrelated donors. The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab. Future trials could determine whether the doses of ATG used in this trial are optimum, and could also provide additional evidence of a low relapse rate after non-myeloablative regimens.
  
  
  BACKGROUND
  The Canadian Institutes of Health Research and Sanofi.
authors.affiliation: McMaster University and Juravinski Hospital and Cancer Centre, Hamilton, ON, Canada. Electronic address: walkeri@mcmaster.ca.
authors.forename: Irwin
authors.initials: I
authors.lastname: Walker
authors.affiliation: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto and Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Panzarella
authors.affiliation: Dalhousie University and Capital District Health Authority Halifax, NS, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Couban
authors.affiliation: Centre Hospitalier Universitaire de Québec, Pavillon Hôtel-dieu de Québec, Québec City, QC, Canada.
authors.forename: Felix
authors.initials: F
authors.lastname: Couture
authors.affiliation: University of Toronto and Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Devins
authors.affiliation: Saskatoon Cancer Centre, Saskatoon, SK, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elemary
authors.affiliation: Université Laval, and CHA Hôpital l'Enfant-Jésus, Québec, Québec City, QC, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gallagher
authors.affiliation: Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Holly
authors.initials: H
authors.lastname: Kerr
authors.affiliation: University of Toronto and Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Kuruvilla
authors.affiliation: University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: St Vincent's Hospital, Sydney, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Moore
authors.affiliation: Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, British Columbia Cancer Agency, and University of British Columbia, BC, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nevill
authors.affiliation: Royal Victoria Hospital, Montreal, QC, Canada.
authors.forename: Gizelle
authors.initials: G
authors.lastname: Popradi
authors.affiliation: Université de Montréal and Maisonneuve-Rosemont Hospital, Montreal, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Roy
authors.affiliation: Michael Cuccione Childhood Cancer Research Program and British Columbia Children's Hospital and Child & Family Research Institute, Vancouver, BC, Canada.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
authors.affiliation: CancerCare Manitoba, Winnipeg, MB, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Szwajcer
authors.affiliation: Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver General Hospital, British Columbia Cancer Agency, and University of British Columbia, BC, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Toze
authors.affiliation: Juravinski Hospital and Cancer Centre, Hamilton, ON, Canada.
authors.forename: Ronan
authors.initials: R
authors.lastname: Foley
mesh_terms: D000328:Adult; D064591:Allografts; D000818:Animals; D000961:Antilymphocyte Serum / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care / Q000379:methods; D011817:Rabbits; D019172:Transplantation Conditioning / Q000379:methods*; D014775:Virus Activation / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D007155:Immunologic Factors; D007166:Immunosuppressive Agents