Phase 1 thiotepa-based conditioning + de-escalated cyclophosphamide (DNA-alkylating immunosuppression) for alloSCT

This Phase 1, open-label transplant-conditioning study tests a thiotepa + busulfan + fludarabine (TBF) backbone before HLA-matched related or unrelated donor peripheral blood stem cell transplantation, paired with a de-escalated post-graft cyclophosphamide (PTCy) strategy to prevent graft-versus-host disease (GVHD). Thiotepa (generic; multiple manufacturers) is a DNA-alkylating agent, busulfan (generic; multiple manufacturers) is a DNA-alkylating agent used for myeloablation, and fludarabine (generic; multiple manufacturers) is a purine analog that inhibits DNA synthesis and provides immunosuppression to facilitate engraftment; cyclophosphamide (generic; multiple manufacturers) is also a DNA-alkylating agent used post-transplant to reduce alloreactive T cells and lower GVHD risk. The trial compares two intensity cohorts (lower-dose vs higher-dose fludarabine) while keeping thiotepa and busulfan dosing consistent, focusing on safety/feasibility signals such as engraftment and early transplant complications. Eligible diseases include transplant-eligible acute leukemias (ALL, AML) and advanced MDS/MPN, where today’s care for appropriate candidates is alloSCT after induction/consolidation (and often targeted agents such as FLT3/IDH inhibitors in AML when indicated) with a conditioning regimen plus GVHD prophylaxis; this study asks whether a TBF platform with less PTCy can preserve disease control and engraftment while reducing toxicity and immune suppression burden.