title: A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease.
abstract: Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (P < .001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Alex F
authors.initials: AF
authors.lastname: Herrera
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Bhavjot
authors.initials: B
authors.lastname: Bindra
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Jones
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikiforow
authors.affiliation: Blood and Marrow Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address: john_koreth@dfci.harvard.edu.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage*; D011446:Prospective Studies; D011719:Pyrazines / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D011241:Prednisone
keywords: Chronic graft-versus-host disease; Graft-versus-host disease; Hematopoietic stem cell transplantation; Proteasome inhibition