Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial

Background Previously, we demonstrated that the addition of anti-human-T-lymphocyte immunoglobulin (ATLG) to standard ciclosporin and methotrexate prophylaxis reduced graft-versus-host disease (GvHD) in adult patients treated with allogeneic haemopoietic cell transplantation from matched unrelated donors without negatively affecting relapse and survival. Since reports on long-term results from randomised trials testing anti-thymocyte globulin are scarce, we performed an extended follow-up of the trial. 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 to receive ciclosporin and methotrexate with or without ATLG. 201 patients who underwent transplantation with peripheral blood (n= 164; 82%) or bone marrow (n= 37; 18%) grafts after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATLG n= 103, non-ATLG n= 98). We assessced chronic GvHD, non-relapse mortality, relapse, relapse mortality, disease-free survival, overall survival, severe GvHD-free (acute GvHD III-IV, and extensive chronic GvHD) and relapse-free survival, and time under immunosuppressive therapy after long-term follow-up. The trial is registered with the German Clinical Trials Register (DRKS00000002), ClinicalTrials. gov (NCT00655343), and EudraCT (2004-000232-91). Findings Median follow-up was 8 . 6 years (IQR 8 . 0-9 . 3). Only patients at risk for chronic GvHD (ie, patients who were alive and without a second transplant at 100 days) were included in the analyses of chronic GvHD (90 patients in the ATLG group, 80 patients in the non-ATLG group). At 8 years, the incidence of extensive chronic GvHD was 14% (95% CI 8-29) in the ATLG group versus 52% (42-64) in the non-ATLG group (adjusted hazard ratio [HR] 0 . 18, 95% CI 0 . 09-0 . 34; p < 0 . 0001). Non-relapse mortality was 21% (95% CI 14-30) versus 34% (26-45; adjusted HR 0 . 66, 95% CI 0 . 38-1 . 16; p= 0 . 15), incidence of relapse was 35% (95% CI 27-46) versus 30% (22-41; adjusted HR 1 . 17, 95% CI 0 . 71-1 . 93; p= 0 . 54), relapse mortality was 31% (95% CI 23-41) versus 29% (21-40; adjusted HR 1 . 03, 95% CI 0 . 61-1 . 76; p= 0 .90), disease-free survival was 44% (95% CI 35-54) versus 36% (27-46) (adjusted HR 0 . 91, 95% CI 0 . 63-1 . 31; p= 0 . 60), overall survival was 49% (95% CI 39-59) versus 37% (27-47; adjusted HR 0 . 82, 95% CI 0 . 56-1 . 20; p= 0 . 31), and severe GvHD-free and relapse-free survival was 34% (25-43) versus 13% (7-21) (adjusted HR 0 . 55, 95% CI 0 .39-0 .76; p= 0 . 0003). The probability of being alive and free of immunosuppressive therapy was 47% (95% 37-57) in the ATLG group and 11% (5-18) in the non-ATLG group at 8 years. Interpretation ATLG in addition to standard ciclosporin and methotrexate as GvHD prophylaxis improves severe GvHD-free and relapse-free survival in the long term. The use of ATLG in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression.