title: Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation.
abstract: OBJECTIVE
  HLA-mismatched unrelated donor (MMUD) hematopoietic stem-cell transplantation (HSCT) is associated with increased graft-versus-host disease (GVHD) and impaired survival. In reduced-intensity conditioning (RIC), neither ex vivo nor in vivo T-cell depletion (eg, antithymocyte globulin) convincingly improved outcomes. The proteasome inhibitor bortezomib has immunomodulatory properties potentially beneficial for control of GVHD in T-cell-replete HLA-mismatched transplantation.
  
  
  METHODS
  We conducted a prospective phase I/II trial of a GVHD prophylaxis regimen of short-course bortezomib, administered once per day on days +1, +4, and +7 after peripheral blood stem-cell infusion plus standard tacrolimus and methotrexate in patients with hematologic malignancies undergoing MMUD RIC HSCT. We report outcomes for 45 study patients: 40 (89%) 1-locus and five (11%) 2-loci mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5 months (range, 17.4 to 59.6 months) follow-up.
  
  
  RESULTS
  The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22% (95% CI, 11% to 35%). One-year cumulative incidence of chronic GVHD was 29% (95% CI, 16% to 43%). Two-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 11% (95% CI, 4% to 22%) and 38% (95% CI, 24% to 52%), respectively. Two-year progression-free survival and overall survival were 51% (95% CI, 36% to 64%) and 64% (95% CI, 49% to 76%), respectively. Bortezomib-treated HLA-mismatched patients experienced rates of NRM, acute and chronic GVHD, and survival similar to those of contemporaneous HLA-matched RIC HSCT at our institution. Immune recovery, including CD8(+) T-cell and natural killer cell reconstitution, was enhanced with bortezomib.
  
  
  CONCLUSIONS
  A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, 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: Sean M
authors.initials: SM
authors.lastname: McDonough
authors.forename: Bhavjot
authors.initials: B
authors.lastname: Bindra
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
mesh_terms: D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006680:HLA Antigens; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006648:Histocompatibility; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage; D061349:Unrelated Donors
chemical_list: D000961:Antilymphocyte Serum; D001897:Boronic Acids; D006680:HLA Antigens; D011719:Pyrazines; D000069286:Bortezomib; D016559:Tacrolimus; D008727:Methotrexate