Phase 2 automated VMAT-based TMLI conditioning refines marrow / lymphoid-targeted irradiation for allo-HCT.

Stanford University is running this non-randomized, open-label Phase 2 study to confirm feasibility and safety of an automated total marrow and lymphoid irradiation (TMLI) platform when embedded into a previously validated reduced-toxicity conditioning approach for allogeneic hematopoietic cell transplant (allo-HCT). Patients receive fludarabine (a purine analog that inhibits DNA synthesis) plus cyclophosphamide (an alkylator that crosslinks DNA) together with VMAT-based TMLI (external-beam radiation conformally targeting marrow and lymphoid tissues), followed by allogeneic peripheral blood stem cell transplantation. GVHD prophylaxis uses post-transplant cyclophosphamide (PTCy; immunomodulatory T-cell depletion), then mycophenolate mofetil (IMPDH inhibitor blocking lymphocyte proliferation) and tacrolimus (calcineurin inhibitor suppressing T-cell activation). Cohort A focuses on first allo-HCT for high-risk myeloid malignancies (AML with adverse biology or persistent blasts; MDS/MPN/MPN with high blasts and/or TP53 mutation, noting TP53 alterations are a clinically important minority but strongly prognostic), while Cohort B enrolls patients relapsing after a prior allo-HCT with a lower-dose TMLI regimen. The key angle is operational: automation aims to make technically demanding TMLI planning/QA faster and more scalable without losing organ-sparing advantages; today’s care for these high-risk AML/MDS/MPN settings is induction/salvage systemic therapy followed by allo-HCT using chemotherapy-based conditioning (with or without broader-field irradiation) and PTCy-based GVHD prophylaxis in many centers.