title: A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial.
abstract: Hematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell-replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.).
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Electronic address: john_koreth@dfci.harvard.edu.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Paulina B
authors.initials: PB
authors.lastname: Lange
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Bhavjot
authors.initials: B
authors.lastname: Bindra
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Carol G
authors.initials: CG
authors.lastname: Reynolds
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Marie J
authors.initials: MJ
authors.lastname: Chammas
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Brett
authors.initials: B
authors.lastname: Glotzbecker
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikiforow
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Division of Blood and Marrow Transplantation, University of Minnesota Masonic Cancer Center and Department of Pediatrics, Minneapolis, Minnesota.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
mesh_terms: D000328:Adult; D000069286:Bortezomib / Q000627:therapeutic use*; D002066:Busulfan / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D016019:Survival Analysis; D016559:Tacrolimus / Q000627:therapeutic use; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D019653:Myeloablative Agonists; D000069286:Bortezomib; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D016559:Tacrolimus; D008727:Methotrexate
keywords: Allogeneic; HLA mismatch; Myeloablative; Proteasome inhibitor; T cell replete; Transplantation