Medium-dose etoposide, cyclophosphamide and total body irradiation conditioning potentiates anti-leukemia immunity in adults with acute lymphoblastic leukemia without aggravating graft-versus-host disease

Medium-dose etoposide (ETP), cyclophosphamide (CY) and total body irradiation (TBI) is a beneficial conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in adults with acute lymphoblastic leukemia (ALL), especially with high-risk ALL, as compared with CY and TBI conditioning. ETP may enhance immunogenicity of leukemia-associated antigens through increased expression of major histocompatibility antigen complex class I, leading to cross-priming of T cells by dendritic cells and generating leukemia-specific cytotoxic T cells. Furthermore, ETP can eliminate activated effector T cells, sparing naive and memory T cells, accompanied with depletion of regulatory T cells. These mechanisms are supposed to lead to inhibit immune escape of leukemia cells and enhance anti-leukemia immunity in addition to direct cytotoxicity of ETP, followed by an efficient eradication of leukemia cells. According to the findings of pharmacokinetics studies, spreading the administration of low-dose ETP may be more efficacious than non-spreading administration, to induce a potent anti-leukemia immunity without aggravating graft-versus-host disease and transplant-related toxicity. In the present review, I discuss the immunological aspects elicited by the addition of medium-dose ETP to the CY/TBI conditioning and the possible positioning of allo-HCT with this conditioning in adults with ALL, considering recent progress in non-HCT treatment including bispecific antibody-based therapy.(c) 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.