title: Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation.
abstract: Advances in haploidentical bone marrow transplantation (h-BMT) have drastically broadened the treatment options for patients requiring BMT. The possibility of significantly reducing the complications resulting from graft-versus-host disease (GvHD) with the administration of post-transplant cyclophosphamide (PT-CY) has substantially improved the efficacy and applicability of T cell-replete h-BMT. However, higher frequency of disease recurrence remains a major challenge in h-BMT with PT-CY. There is a critical need to identify novel strategies to prevent GvHD while sparing the graft-versus-leukaemia (GvL) effect in h-BMT. To this end, we evaluated the impact of bendamustine (BEN), given post-transplant, on GvHD and GvL using clinically relevant murine h-BMT models. We provide results indicating that post-transplant bendamustine (PT-BEN) alleviates GvHD, significantly improving survival, while preserving engraftment and GvL effects. We further document that PT-BEN can mitigate GvHD even in the absence of Treg. Our results also indicate that PT-BEN is less myelosuppressive than PT-CY, significantly increasing the number and proportion of CD11b(+) Gr-1(hi) cells, while decreasing lymphoid cells. In vitro we observed that BEN enhances the suppressive function of myeloid-derived suppressor cells (MDSCs) while impairing the proliferation of T- and B-cells. These results advocate for the consideration of PT-BEN as a new therapeutic platform for clinical implementation in h-BMT.
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, Arizona.
authors.forename: Jessica
authors.initials: J
authors.lastname: Stokes
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, Arizona.
authors.forename: Emely A
authors.initials: EA
authors.lastname: Hoffman
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, Arizona.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, Arizona.|Department of Immunobiology, University of Arizona, Tucson, Arizona.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Larmonier
authors.affiliation: Department of Pediatrics, University of Arizona, Tucson, Arizona.|Department of Immunobiology, University of Arizona, Tucson, Arizona.|Department of Medicine, University of Arizona, Tucson, Arizona.|Department of Pathology, University of Arizona, Tucson, Arizona.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Katsanis
mesh_terms: D000818:Animals; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage* / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000379:methods*; D003520:Cyclophosphamide / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D006648:Histocompatibility / Q000276:immunology; D007165:Immunosuppression Therapy; D051379:Mice; D014184:Transplantation, Homologous
chemical_list: D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride
keywords: bendamustine; bone marrow transplantation; cyclophosphamide; graft-versus-host disease; graft-versus-leukaemia