A randomized, multicenter Phase II trial to compare prophylaxis of graft versus host disease with tacrolimus and mycophenolate mofetil versus ruxolitinib after post-transplant cyclophosphamide.

OBJECTIVES: Posttransplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is an emerging standard of care in allogeneic hematopoietic cell transplantation (HCT), however, it should be combined with other immunosuppressive agents in unrelated and haploidentical allografts. These combinations have not been previously compared in randomized clinical trials. We compared most common combination of PTCy, tacrolimus (Tac) and mycophenolate mofetil (MMF) to a new calcineurin-free combination of PTCy and ruxolitinib (PTCy-Ruxo). METHODS: The multicenter prospective open-label phase II non-inferiority randomized trial compared GVHD PTCy-Ruxo prophylaxis to PTCy-Tac-MMF in unrelated and haploidentical donor HCT. The study recruited 128 adult patients with acute myeloid leukemia and acute lymphoblastic leukemia in complete remission. Patients were randomized 1:1 and stratified by donor type and disease risk index. PTCy in both groups was administered intravenously at 50 mg/kg on days +3 and +4. Ruxolitinib was given orally at 5 mg TID during conditioning and from day+5 to 21 after HCT, and at 5 mg BID from day+22 to 150. Tac was targeted for a 5-15 ng/ml concentration. MMF was administered at 30 mg/ kg/day per os in 10/10 HLA compatible HCT and 45 mg/kg/day per os in <10/10 HLA compatible HCT from D+5 to D+35 The aim was to demonstrate non-inferiority of PTCy-Ruxo for prevention of acute grade II-IV compared with PTCy-Tac-MMF with a non-inferiority-margin of 10% and one-sided type 1 error of 2·5%.The trial was completed and registered at ClinicalTrials.gov, NCT04669210. RESULTS: The study met its primary endpoint of non-inferior efficacy of PTCy-Ruxo GVHD prophylaxis. Cumulative incidence of acute GVHD grade II-IV at 125 days was 12.9% vs 21.2% in PTCy-Ruxo and PTCy-Tac-MMF groups respectively (superiority p=0.20, non-inferiority p=0.0041). The acute GVHD II-IV risk difference was -8.3% (95%CI -21.2% to 4.6%) for PTCy-Ruxo. The study met its secondary endpoints of non-inferior chronic GVHD cumulative incidence at 2 years and a better safety profile with PTCy-Ruxo prophylaxis. Cumulative incidence of moderate and severe chronic GVHD was 24.2% vs 39.5% (superiority p=0.09, non-inferiority p= 0.0012). The moderate and severe chronic GVHD risk difference was -15.2% (95%CI -31.1% to 0.7%) for PTCy-Ruxo. PTCy-Ruxo prophylaxis was associated with reduced incidence of grade 2-4 acute kidney injury (1.6% vs 12.1%, p=0.02), endothelial complications (1.6% vs 13.6%, p=0.01), and severe poor graft function (21.1% vs 42.6%, p=0.01). No differences in overall survival (80.6% vs 72.5%, p=0.28) or GVHD-relapse-free survival were observed between groups (61.3% vs 48.1%, p=0.19). CONCLUSION: The study demonstrated non-inferior efficacy of PTCy-Ruxo GVHD prophylaxis compared to PTCy-Tac-MMF with a 10% margin in unrelated and haploidentical HCT. Given the improved safety profile of PTCy-Ruxo compared with PTCy-Tac-MMF this regimen warrants further exploration as an alternative to calcineurin-based regimens.