Phase 2 haploidentical HSCT using cyclophosphamide/busulfan or fludarabine/TBI conditioning (DNA-damaging alkylators)

This National Cancer Institute (NIH Clinical Center) Phase 2, prospective, open-label transplant protocol tests whether individualized (“tailored”) dosing of conditioning chemotherapy and key supportive-care drugs can improve disease-free survival versus historical outcomes in germline RUNX1–predisposition myeloid malignancies. Patients (ages 4–70) undergo haploidentical allogeneic hematopoietic stem cell transplantation with either myeloablative cyclophosphamide (DNA crosslinking alkylator) + busulfan (DNA crosslinking alkylator) conditioning, or reduced-intensity fludarabine (purine analog inhibiting DNA synthesis) + cyclophosphamide plus total body irradiation, followed by graft-versus-host disease prophylaxis with tacrolimus (calcineurin inhibitor) and mycophenolate mofetil (IMPDH inhibitor). The scientific angle is the RUNX1-focused, mutation-restricted prospective design—important because RUNX1 familial platelet disorder confers a high lifetime risk of hematologic malignancy (~35–50%), yet much transplant guidance is retrospective and heterogeneous. Today’s care for RUNX1-associated MDS/AML typically uses AML-like induction/bridging therapy as needed and then allogeneic HSCT (often with matched donors when available); this study focuses on expanding haploidentical access while optimizing exposure and toxicity management in a genetically defined population.