Short Course of Post-Transplantation Cyclophosphamide and Bortezomib for Graft-versus-Host Disease Prevention after Allogeneic Peripheral Blood Stem Cell Transplantation Is Feasible and Yields Favorable Results: A Phase I Study

Ahmad Samer Al-Homsi*, Kelli Cole, Marlee Bogema, Ulrich Duffner, Stephanie Williams, Aly Mageed

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

An effective graft-versus-host disease (GVHD) preventative approach that preserves the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation (HSCT) remains elusive. Standard GVHD prophylactic regimens suppress T cells indiscriminately and are suboptimal. Conversely, post-transplantation high-dose cyclophosphamide selectively destroys proliferating alloreactive T cells, allows the expansion of regulatory T cells, and induces long-lasting clonal deletion of intrathymic antihost T cells. It has been successfully used to prevent GVHD after allogeneic HSCT. Bortezomib has antitumor activity on a variety of hematological malignancies and exhibits a number of favorable immunomodulatory effects that include inhibition of dendritic cells. Therefore, an approach that combines post-transplantation cyclophosphamide and bortezomib seems attractive. Herein, we report the results of a phase I study examining the feasibility and safety of high-dose post-transplantation cyclophosphamide in combination with bortezomib in patients undergoing allogeneic peripheral blood HSCT from matched siblings or unrelated donors after reduced-intensity conditioning. Cyclophosphamide was given at a fixed dose (50 mg/kg on days+3 and+4). Bortezomib dose was started at .7 mg/m2, escalated up to 1.3 mg/m2, and was administered on days 0 and+3. Patients receiving grafts from unrelated donors also received rabbit antithymocyte globulin. The combination was well tolerated and allowed prompt engraftment in all patients. The incidences of acute GVHD grades II to IV and grades III and IV were 20% and 6.7%, respectively. With a median follow-up of 9.1 months (range, 4.3 to 26.7), treatment-related mortality was 13.5% with predicted 2-year disease-free survival and overall survival of 55.7% and 68%, respectively. The study suggests that the combination of post-transplantation cyclophosphamide and bortezomib is feasible and may offer an effective and practical GVHD prophylactic regimen. The combination, therefore, merits further examination.

Original languageEnglish (US)
Pages (from-to)1315-1320
Number of pages6
JournalBiology of Blood and Marrow Transplantation
Volume21
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

Keywords

  • Allogeneic blood and marrow transplantation
  • Bortezomib
  • Graft-versus-host disease prophylaxis
  • Post-transplantation cyclophosphamide

ASJC Scopus subject areas

  • Hematology
  • Transplantation

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