title: Treatment of chronic graft-versus-host disease with bortezomib.
abstract: Chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) has emerged as a predominant complication following HSCT and has a distinct etiology. We and others have previously demonstrated that bortezomib, a proteasome inhibitor, can prevent but not treat acute GVHD in mice. To assess the effects of bortezomib on cGVHD, a mouse minor histocompatibility antigen-mismatched strain combination was used to mimic clinical cGVHD sclerodermatous pathogenesis and phenotype. Treatment of ongoing cGVHD with bortezomib ameliorated cutaneous lesions, which were also associated with a reduction in total numbers of germinal center B cells and lower B-cell activating factor gene expression levels in cutaneous tissues. Importantly, lymphoma-bearing mice receiving allogeneic HSCT with bortezomib preserved graft-versus-tumor (GVT) effects. Based on these animal studies, we initiated an intrapatient dose escalation clinical trial in patients with extensive steroid-intolerant, dependent, or resistant cGVHD. Marked clinical improvement was observed in patients, which was also associated with reductions of peripheral B cells and minimal toxicity. These results indicate that bortezomib can be of significant use in the treatment of cGVHD and may also allow for maintenance of GVT. This trial was registered at www.clinicaltrials.gov as #NCT01672229.
authors.affiliation: Department of Dermatology and.
authors.forename: Chien-Chun Steven
authors.initials: CC
authors.lastname: Pai
authors.affiliation: Department of Pathology, School of Medicine, University of California, Davis, Sacramento, CA;
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Dermatology and.
authors.forename: Annie
authors.initials: A
authors.lastname: Mirsoian
authors.affiliation: Department of Dermatology and.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grossenbacher
authors.affiliation: Department of Dermatology and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tellez
authors.affiliation: Department of Dermatology and.
authors.forename: Erik
authors.initials: E
authors.lastname: Ames
authors.affiliation: Institute of Hematology, Zhengzhou University People's Hospital, Zhengzhou, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Dermatology and.
authors.forename: Jared
authors.initials: J
authors.lastname: Jagdeo
authors.affiliation: Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Dermatology and Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Abedi
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011719:Pyrazines / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000473:pathology; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib