A Randomized Prospective Multicenter Phase III Trial Comparing Standard GvHD Prophylaxis with Cyclosporine and Methotrexate with Additional Pretransplant ATG Fresenius (ATG-F) in Allogeneic Stem Cell Transplantation from Matched Unrelated Donors

Graft versus host disease is a major cause of morbidity and mortality after allogeneic stem cell transplantation from unrelated donors. Strategies using intensified GvHD prophylaxis including T cell depletion did not result in better outcome due to increased risks of infection and relapse. The use of ATG in the conditioning regimen for in vivo-Tcell depletion for GVHD prophylaxis has been reported by several groups but not been tested in a large prospective randomized trial. Here we report on results from the first large prospective, randomized, multicenter, open-label, phase III trial comparing standard GvHD prophylaxis with cyclosporine A (CyA) and short course methotrexate (Mtx) days +1, +3, +6, +11 (15/10/10/10 mg/m²) with or without 3×20mg/kg ATG-Fresenius (ATG-F) after a median follow-up time of two years.

Between 2003 and 2007, 201 patients, median age 40 (range 18–60) years with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1^st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94), were transplanted from HLA-A and -B (2 digit), DRB1, DQB1 (4 digit) identical unrelated donors after highdose myeloablative conditioning with marrow (n=37) or PBSC (n=164) grafts. Median follow up time was 732.5 (25%-quartile 604, 75%-quartile 1097) days. For treatment comparisons with regard to the occurrence of aGvHD grade III-IV or death within 100 days post Tx, logistic regression adjusted for status of disease, source of stem cells, and center was used. For treatment comparisons with regard to time-to-event variables, cumulative incidence rates considering relapse and death as competing events were estimated, and Cox regression modelling the event-specific hazard rates and adjusting for status of disease and source of stem cells was used.

Engraftment with WBC > 1000/μl was achieved in 97% in the ATG-F group after median 26 days, and in 95% in the control group after median 19 days (p<0.0001). At day +100, the rate of patients experiencing the primary efficacy endpoint-severe aGvHD (grade III–IV) or death - was 21.4% in the CyA/Mtx/ATG-F arm versus 33.7% in the CyA/Mtx only arm (p=0.1286). Incidence of grade III–IV acute GvHD was 11.7% in the ATG-F arm and 24.5% in the control group (p=0.054), grade II–IV aGvHD was 33.0% vs. 51.0% (p=0.0108), and grade I–IV aGvHD was 56.3% vs. 74.5% (p=0.0073). Incidence of chronic GvHD (limited and extensive) after two years was 30.8% in the ATG-F group versus 58.8% in the control group (p<0.0001). Incidence of extensive chronic GvHD after two years was 12.2% in the ATG-F group versus 42.6% in the control group (p<0.0001). Disease-free survival (DFS) after two years was 51.6% in the ATG-F and 47.5% in the control group (p=0.65). Incidence of relapse/progression after two years was 28.9% in the ATG-F and 23.6% in the control group (p=0.55). Incidence of death without former relapse/progression (TRM) after two years was 19.6% in the ATG-F and 28.9% in the control group (p=0.198). Overall survival (OS) after two years was 59.2% in the ATG-F and 51.9% in the control group (p=0.47). Number of infections per follow up year was 4.54 in the ATG-F and 4.76 and in the control group.

The addition of ATG-F to standard CyA/Mtx prophylaxis results in decreased incidence of acute and chronic GvHD without increase of relapse or TRM rates. This is the first randomized trial answering the long-standing question regarding the beneficial effect of additional ATG-F to a standard GvHD prophylaxis. A reduction of GvHD without compromising survival could be demonstrated.