A phase 1 trial utilizing TMI with fludarabine-melphalan in patients with hematologic malignancies undergoing second allo-SCT.

Relapse after allogeneic stem cell transplantation (allo-SCT) remains the primary cause of treatment failure. A second SCT can result in long-term survival in a subset of patients, but the relapse rate remains high. We conducted a single center, phase I, modified 3+3 dose-escalation study of the feasibility of combining intensity-modulated total marrow irradiation (IM-TMI) with fludarabine and melphalan for conditioning. Between December 2015 and May 2020, 21 patients with relapsed hematologic disease undergoing second or greater allo-SCT were treated with IM-TMI doses of 6Gy, 9Gy, or 12Gy. Dose-limiting toxicity (DLT) was defined as a Grade 3 or higher treatment-related adverse event; mucositis was the primary DLT. The median times to neutrophil and platelet engraftments were 10 and 18 days, respectively. The 1-year cumulative incidence of GVHD was 65% (95% CI, 38-83%). The non-relapse mortality at two years was 17% (95% CI, 4-39%). Cumulative incidence of relapse at two years was 35% (95% CI, 13-58%). 2-year progression-free survival and overall survival were 48% and 50%, respectively. We conclude that combining IM-TMI with fludarabine-melphalan is feasible. We recommend 12Gy of IM-TMI with fludarabine-melphalan for second SCT, though 9Gy may be used for older or underweight patients. ClinicalTrials.gov Identifier: NCT00988013.