title: Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone.
abstract: Lapses in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) warrant novel approaches. Such approaches include, among others, the use of post-transplantation cyclophosphamide (PTC) and proteasome inhibitors. Although PTC alone consistently produces low rates of chronic GVHD, the incidence of acute GVHD remains significant. Inversely, prolonged post-transplantation administration of proteasome inhibitors carries a risk of paradoxical aggravation of GVHD. We examined whether the combination of cyclophosphamide and ixazomib addresses the limitations of each of these agents when used alone to prevent GVHD in mice subjected to allogeneic HSCT across MHC barriers. We chose ixazomib, an orally bioavailable proteasome inhibitor, because of its favorable physiochemical characteristics. The combination of cyclophosphamide and ixazomib improved overall survival of mice in comparison to an untreated control group and to groups receiving either cyclophosphamide alone or ixazomib alone. Furthermore, cyclophosphamide prevented the surge of IL-1β, GVHD aggravation, and sudden death associated with prolonged administration of ixazomib after HSCT. Finally, we demonstrated that although ixazomib was administered before cyclophosphamide, it did not impair the preferential depletion of proliferating as opposed to resting donor T cells. Our data suggest that the combination of cyclophosphamide and ixazomib for the prevention of GVHD after allogeneic HSCT is promising and merits further investigation in clinical trials.
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, Michigan; Michigan State University College of Human Medicine, Grand Rapids, Michigan. Electronic address: A.Samer.Al-Homsi@SpectrumHealth.org.
authors.forename: Ahmad Samer
authors.initials: AS
authors.lastname: Al-Homsi
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, Michigan.
authors.forename: Austin
authors.initials: A
authors.lastname: Goodyke
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, Michigan.
authors.forename: Michael
authors.initials: M
authors.lastname: McLane
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, Michigan.
authors.forename: Sarah
authors.initials: S
authors.lastname: Abdel-Mageed
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, Michigan.
authors.forename: Kelli
authors.initials: K
authors.lastname: Cole
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, Michigan.
authors.forename: Marlee
authors.initials: M
authors.lastname: Muilenburg
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, Michigan.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D001896:Boron Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D007421:Intestine, Small / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011828:Radiation Chimera; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000637:transplantation
chemical_list: D001896:Boron Compounds; D016207:Cytokines; D061988:Proteasome Inhibitors; C548400:ixazomib; D003520:Cyclophosphamide; D005998:Glycine
keywords: Graft-versus-host disease; Ixazomib; Post-transplantation cyclophosphamide; Proteasome inhibitors