Post-Transplant Cyclophosphamide, Tacrolimus or Cyclosporine a and Mycophenolate Mofetil Compared to Anti-Thymocyte Globulin tacrolimus or Cyclosporine a and Methotrexate Combinations As Graft- versus -Host Disease Prophylaxis Post Allogeneic Stem Cell Transplantation from Sibling and Unrelated Donors in Patients with Acute Myeloid Leukemia: a Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background The BMT CTN 1703 phase III study compared post-transplant cyclophosphamide with tacrolimus with mycophenolate mofetil (PTCy/TAC/MMF) to TAC /methotrexate (MTX) as GVHD prophylaxis post allogeneic transplantation (HSCT), demonstrating a lower incidence of severe acute (a) GVHD and chronic (c) GVHD and better GRFS. The control arm did not include ATG, used in many centers for GVHD prophylaxis. Methods Study aim was to compare PTCy with TAC or cyclosporine A (CSA) and MMF (PTCy/TAC or CSA & MMF) to ATG combined with TAC or CSA and MTX (ATG/TAC or CSA & MTX) in AML patients (pts) undergoing HSCT from matched siblings (MSD) or 9-10/10 unrelated donor (UD) in CR1. Statistical tests included a multivariate analysis (MVA) using a Cox proportional-hazards regression model for main outcomes. Results 6050 pts met the inclusion criteria, 402 received PTCy/TAC or CSA & MMF and 5648 received ATG/TAC or CSA & MTX. Median follow-up was 23.4 (IQR, 20.3-24.9) and 41.8 (IQR, 39.6-43.3) months (p<0.0001). Pts in the PTCy/TAC or CSA & MMF group were younger, with a median age of 48.7 (range 18-5.6) vs. 51.5 (8-77.8) years (y) (p=0.024). The cytogenetic risk was categorized as intermediate (70.9% vs. 67.1%), adverse (22.2% vs. 25.7 %), and favorable (6.9% vs. 7.2%) for pts in the PTCy/TAC or CSA & MMF and ATG/TAC or CSA & MTX groups, respectively (p=0.35) (data missing for 2214 pts). More pts in the PTCy/TAC or CSA & MMF group received RIC 51.5% vs. 41.1% in the ATG/TAC or CSA & MTX group, respectively (p<0001). Day 60 neutrophil engraftment (ANC ≥0.5 × 109/L) was 98.7% vs. 98.6% (p=0.84). Day 180 incidence of a GVHD grade II-IV and III-IV was 21.2% vs. 20.4% (p=0.92) and 8.1% vs. 6% (p=0.1), in pts receiving PTCy/TAC or CSA & MMF vs. the ATG/TAC or CSA & MTX. The 2- y total and extensive chronic (c) GVHD were 33.7% vs. 30% (p=0.09) and 10.7 % vs. 11.2% (p=0.81). GVHD was the cause of death in 11.6% vs. 13.9% of pts who died. In the MVA, both aGVHD (grade II-IV or III-IV) and cGVHD (total or extensive) did not differ between the groups with hazard ratios (HRs) =1.15 (95% CI 0.86-1.53, p=0.35), HR=0.87 (95% CI 0.56-1.34, p=0.52), HR=0.91 (95% CI 0.7-1.18, p=0. 47 and HR=1.51 (95% CI 0.96-2.36, p=0.074). Two-y NRM was significantly lower in pts that received PTCy/TAC or CSA & MMF vs ATG/TAC or CSA & MTX, HR=1.57 (95% CI 1.07-2.3, p=0.022). Other HSCT outcome parameters did not differ between the groups. The HR for 2-y RI was 0.99 (95% CI 0.77-127, p=0. 93). The HRs for 2-y LFS, OS, and GRFS were HR=1.15 (95% CI 0.94-1.42, p<0.18), HR=1.18 (95% CI 0.94-1.49, p=0.16) and HR=1.12 (95% CI 0.93-1.36, p=0.22). Conclusions In this retrospective analysis, comparing PTCy in combination with TAC or CSA and MMF to ATG in combination with TAC or CSA and MTX as GVHD prophylaxis, we observed a similar incidence and severity of both aGVHD and cGVHD. NRM was significantly lower with PTCy, while all other transplant outcome parameters were similar.