Phase 2 TMLI conditioning + fludarabine/melphalan; IMRT marrow/lymphoid targeting + DNA-damaging chemo

City of Hope Medical Center is running this Phase 2 study testing whether total marrow and lymphoid irradiation (TMLI)—an intensity-modulated radiation approach that concentrates dose to marrow, lymph node chains, and spleen while relatively sparing other organs—can safely improve conditioning for matched-donor allogeneic peripheral blood stem cell transplant in older patients with relapsed/refractory AML or high-risk MDS. The regimen combines TMLI (external-beam irradiation) with fludarabine (a purine analog that inhibits DNA synthesis) and melphalan (an alkylating agent that crosslinks/damages DNA), followed by donor PBSC-HCT. Supportive/adjunct components include palifermin (a recombinant keratinocyte growth factor/FGF pathway agonist used to reduce mucositis) plus tacrolimus (calcineurin inhibitor) and sirolimus (mTOR inhibitor) for GVHD prophylaxis. The key angle is whether targeted marrow/lymphoid radiation can intensify anti-leukemia effect without the toxicity burden of traditional total body irradiation or fully myeloablative chemo in an older, harder-to-treat population. Today’s care for older relapsed/refractory AML or high-risk MDS aiming for cure is salvage therapy to reach cytoreduction when feasible, then allogeneic transplant using reduced-intensity or melphalan-based conditioning, with outcomes limited by relapse risk and regimen-related toxicity.