Improved Clinical Outcome After Total Marrow Irradiation Conditioning Stem Cell Transplantation for Hematologic Malignancies

Abstract

Radiation is an effective component of the transplantation conditioning regimen, for both its immunosuppressive properties and its direct antileukemia activity. Cyclophosphamide combined with total body irradiation (Cy/TBI) is the most widely used myeloablative conditioning regimen for allotransplants. We have been investigating targeted total marrow irradiation (TMI) as a more precise form of TBI delivery, in combination with cyclophosphamide, versus Cy/TBI in patients with hematologic malignancies. A prospective parallel-controlled cohort study was conducted among patients with hematologic malignancies who first underwent allogeneic peripheral blood stem cell transplantation preconditioned with TBI or TMI at our center. Eligible patients were diagnosed with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome with excess blasts. Patients were assigned (1:1) to receive either TBI conditioning performed at 5Gy × 2 QD (TBI group) or TMI regimen scheduled to 4Gy × 3 QD (TMI group). Our primary objective was to determine the safety and efficacy of TMI regimen and its potential advantage of organ sparing.

Between March 2014 and June 2018, 56 eligible study participants were assigned to either the TBI group (n = 28) or the TMI group (n = 28). Patients in both arms were well balanced for gender, age, diagnosis, risk stratification, pretransplant remission status, HLA ty**, and donor source. All patients achieved successful hematopoietic reconstitution. A 1.41- to 7.45-fold reduction in median organ doses was observed with TMI compared with TBI. There was no statistical difference in overall grade II–IV acute GVHD between two arms (39.3% vs. 32.1%, p = 0.781). The cumulative incidence of chronic GVHD was higher in TBI arm (60.7% vs. 46.4%, p = 0.330). Although not statistically significant, the TMI arm showed better GVHD/relapse-free survival (GRFS) (50% vs. 32.1%, p = 0.150), decreased transplant-related mortality (TRM) (0% vs. 7.1%, p = 0.491), and better 1-year overall survival (OS) (85.7% vs. 67.9%, p = 0.352). Notably, TMI arm showed a significant lower relapse rate (3.6% vs. 32.1%, p = 0.012) and better 1-year relapse-free survival (RFS) (96.4% vs. 67.9%, p = 0.018). Of 18 female patients, 11 (61.1%) in TMI arm resumed menses at a median of 7 months (range 2–12). No menstrual recovery was observed in patients receiving TBI. Ovarian recovery rate in TMI group after transplantation was significantly higher than that in TBI group (61.1% vs. 0, p < 0.0001). TMI conditioning showed superior transplantation efficacy compared with TBI. Overall, TMI appeared to have a favorable tolerability profile compared with TBI. TMI regimen was associated with improved RFS and significant ovarian protection.