title: Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors.
abstract: Graft-versus-host disease (GVHD) is a significant complication of allogeneic stem cell transplantation (alloSCT). The proteasome inhibitor bortezomib has immunomodulatory properties of potential benefit for GVHD control. We undertook a phase 1 trial of bortezomib, tacrolimus, and methotrexate for GVHD prophylaxis after reduced-intensity conditioning alloSCT using human leukocyte antigen-mismatched unrelated donors. Twenty-three patients were enrolled. Bortezomib dose levels of 1, 1.3, and 1.5 mg/m2 were evaluated with 5, 3, and 5 patients, respectively. Ten additional patients were accrued at the 1.3 mg/m2 bortezomib dose level. Bortezomib-related toxicity was minimal. With a 12-month median follow-up, grade II-IV acute GVHD occurred in 3 patients, a 180-day cumulative incidence of 13%. Chronic GVHD occurred in 9 patients, a 1-year cumulative incidence of 41%. At 1-year, the nonrelapse mortality was zero, cumulative incidence of relapse/progression was 29%, and overall, progression-free, and event-free survival were 75%, 64%, and 59%, respectively. Bortezomib is a promising novel immunomodulatory agent in allogeneic transplantation. This study was registered at http://www.clinicaltrials.gov as #NCT00369226.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02115, USA. jkoreth@partners.org
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Garcia
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000401:mortality* / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000401:mortality* / Q000628:therapy*; D006801:Humans; D019520:Living Donors; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D033581:Stem Cell Transplantation; D015996:Survival Rate; D016559:Tacrolimus / Q000008:administration & dosage; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D016559:Tacrolimus; D008727:Methotrexate