Total Marrow and Lymphoid Irradiation with Post-Transplantation Cyclophosphamide for Patients with AML in Remission.

Graft-versus-host disease (GVHD) has remained the main cause of post-transplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplantation cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplantation conditioning regimen with a PTCy-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), overall survival (OS), relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose-limiting toxicities. The patient safety lead-in segment followed 3 + 3 dose expansion/(de-)escalation rules based on observed toxicity through day 30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days -4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days 3 and 4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day 90 and then tapered. Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3 or 4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD grade 2 to 4 and moderate-to-severe chronic GVHD were 11.1% and 11.9%, respectively. At a median follow up of 24.5 months, two-year estimates of OS and relapse-free survival were 86.7% and 83.3%, respectively. Disease relapse at 2 years was 16.7%. The estimates of NRM at 2 years was 0%. The GVHD/GRFS rate at 2 years was 59.3% (95% confidence interval, 28.8-80.3). This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe, with no NRM. Preliminary results suggest an improved GRFS rate.