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

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. Findings: 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. Interpretation: 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. Funding: Fresenius Biotech GmbH.