Patients with acute
leukemia who are unable to achieve complete remission prior to allogeneic
hematopoietic stem cell transplantation (SCT) have dismal outcomes, with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-
leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities, but it typically requires intensive immunosuppression with posttransplant
cyclophosphamide (PT-Cy) to prevent lethal
graft-versus-host disease (GVHD). Here, we demonstrate in preclinical models that
glucocorticoid administration from days -1 to +5 inhibits
alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T cell priming and subsequent expansion therein. In contrast, direct
glucocorticoid signaling of donor T cells promotes
chemokine and
integrin signatures permissive of preferential circulation and migration into the BM, promoting donor T cell residency. This results in significant reductions in GVHD while promoting potent GVL effects; relapse in recipients receiving
glucocorticoids, vehicle, or PT-Cy was 12%, 56%, and 100%, respectively. Intriguingly, patients with
acute myeloid leukemia not in remission who received unmanipulated haplo-SCT and peritransplant
glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%; 95% CI, 18%-47%) with high overall survival at 3 years (58%; 95% CI, 38%-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable
leukemia that could be studied in prospective randomized trials.