title: Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial.
abstract: BACKGROUND
  Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F).
  
  
  METHODS
  Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III-IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343.
  
  
  RESULTS
  The number of patients in the ATG-F group who had severe aGVHD grade III-IV or who died within 100 days of transplantation was 12 and 10 (21.4%, 95% CI 13.4-29.3), respectively, compared with 24 and nine (33.7%, 24.3-43.0) patients, respectively, in the control group (adjusted odds ratio 0.59, 95% CI 0.30-1.17; p=0.13). The cumulative incidence of aGVHD grade III-IV was 11.7% (95% CI 6.8-19.8) in the ATG-F group versus 24.5% (17.3-34.7) in the control group (adjusted hazard ratio [HR] 0.50, 95% CI 0.25-1.01; p=0.054), and cumulative incidence of aGVHD grade II-IV was 33.0% (n=34; 95% CI 25.1-43.5) in the ATG-F group versus 51.0% (n=50; 95% CI 42.0-61.9) in the control group (adjusted HR 0.56, 0.36-0.87; p=0.011). The 2-year cumulative incidence of extensive chronic GVHD was 12.2% (n=11; 95% CI 7.0-21.3) versus 42.6% (n=34; 95% CI 33.0-55.0; adjusted HR 0.22, 0.11-0.43; p<0.0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes.
  
  
  CONCLUSIONS
  The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors.
  
  
  BACKGROUND
  Fresenius Biotech GmbH.
authors.affiliation: Department of Hematology and Oncology, Universitätsklinikum Freiburg, Germany. juergen.finke@uniklinik-freiburg.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Bethge
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmoor
authors.forename: Hellmut D
authors.initials: HD
authors.lastname: Ottinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Stelljes
authors.forename: Axel R
authors.initials: AR
authors.lastname: Zander
authors.forename: Liisa
authors.initials: L
authors.lastname: Volin
authors.forename: Tapani
authors.initials: T
authors.lastname: Ruutu
authors.forename: Dominik A
authors.initials: DA
authors.lastname: Heim
authors.forename: Rainer
authors.initials: R
authors.lastname: Schwerdtfeger
authors.forename: Karin
authors.initials: K
authors.lastname: Kolbe
authors.forename: Jiri
authors.initials: J
authors.lastname: Mayer
authors.forename: Johan A
authors.initials: JA
authors.lastname: Maertens
authors.forename: Werner
authors.initials: W
authors.lastname: Linkesch
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.forename: Vladimir
authors.initials: V
authors.lastname: Koza
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Hans-Jochem
authors.initials: HJ
authors.lastname: Kolb
authors.forename: Hartmut
authors.initials: H
authors.lastname: Bertz
authors.forename: Matthias
authors.initials: M
authors.lastname: Egger
authors.forename: Olga
authors.initials: O
authors.lastname: Grishina
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
mesh_terms: D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum / Q000008:administration & dosage* / Q000009:adverse effects; D016572:Cyclosporine / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011446:Prospective Studies; D012044:Regression Analysis; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D008727:Methotrexate