The phase III ALLG BM12 CAST trial: GvHD prophylaxis with PTCy + CsA

Graft-versus-host disease (GvHD) remains a significant challenge despite advances in prophylactic treatments. The current standard GvHD prophylaxis treatment is cyclosporin A (CsA) or tacrolimus + methotrexate (MTX) or mycophenolate mofetil (MMF). During the European Hematology Association (EHA) 2025 Congress, David Curtis presented findings from the phase III ALLG BM12 CAST trial (ACTRN12618000505202) assessing the safety and efficacy of post-transplant cyclophosphamide (PTCy) + CsA vs CsA + MTX in patients undergoing allogeneic hematopoietic stem cell transplantation.¹ The findings were recently published in The New England Journal of Medicine.²

Patients diagnosed with acute myeloid leukemia or acute lymphoblastic leukemia in complete remission 1 or 2 or myelodysplastic leukemia receiving peripheral blood stem cells from a matched sibling donor in a myeloablative or reduced-intensity chemotherapy setting were included (N = 134). Eligible patients were randomized 1:1 to receive PTCy + CsA (n = 66) or CsA + MTX (n = 68). The primary endpoint was GvHD-free, relapse-free survival. Key secondary endpoints included incidence of acute and chronic GvHD, engraftment, non-relapse mortality, and adverse events. Relapse-free survival was assessed in a post hoc exploratory analysis.^1,2

Key learnings

The 3-year GRFS was significantly higher in the PTCy + CsA vs CsA + MTX group (49% vs 14%; HR, 0.42; p < 0.001). 

PTCy + CsA resulted in a significantly higher 2-year RFS rate (74% vs 59%; HR, 0.55; p = 0.045) and a lower CI of Grade 3–4 aGvHD (p = 0.032) and moderate-to-severe cGvHD (p = 0.033) than CsA + MTX.

PTCy + CsA was well tolerated; the only early toxicity was delayed platelet engraftment compared with CsA + MTX (median time to engraftment was 22 vs 18 days, respectively). Incidence of Grade ≥3 AEs in the first 100 days was lower with PTCy + CsA vs CsA + MTX (20% vs 32%). 

PTCy + CsA was superior compared with CsA + MTX in improving GRFS, with a favorable safety profile. It has the potential to offer a more effective, simpler, and more tolerable alternative to standard GvHD prophylaxis in patients with high-risk blood malignancies in low-resource centers.