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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.
Biol Blood Marrow Transplant. 2015 Jul; 21(7):1315-20.BB

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.

Authors+Show Affiliations

Blood and Marrow Transplantation Program, Spectrum Health, Grand Rapids, Michigan; Michigan State University, College of Human Medicine, Grand Rapids, Michigan. Electronic address: A.Samer.Al-Homsi@SpectrumHealth.org.Blood and Marrow Transplantation Program, Spectrum Health, Grand Rapids, Michigan.Blood and Marrow Transplantation Program, Spectrum Health, Grand Rapids, Michigan.Blood and Marrow Transplantation Program, Spectrum Health, Grand Rapids, Michigan; Michigan State University, College of Human Medicine, Grand Rapids, Michigan.Blood and Marrow Transplantation Program, Spectrum Health, Grand Rapids, Michigan; Michigan State University, College of Human Medicine, Grand Rapids, Michigan.Blood and Marrow Transplantation Program, Spectrum Health, Grand Rapids, Michigan; Michigan State University, College of Human Medicine, Grand Rapids, Michigan.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25765556

Citation

Al-Homsi, Ahmad-Samer, et al. "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." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 21, no. 7, 2015, pp. 1315-20.
Al-Homsi AS, Cole K, Bogema M, et al. 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. Biol Blood Marrow Transplant. 2015;21(7):1315-20.
Al-Homsi, A. S., Cole, K., Bogema, M., Duffner, U., Williams, S., & Mageed, A. (2015). 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. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 21(7), 1315-20. https://doi.org/10.1016/j.bbmt.2015.02.008
Al-Homsi AS, et al. 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. Biol Blood Marrow Transplant. 2015;21(7):1315-20. PubMed PMID: 25765556.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Al-Homsi,Ahmad-Samer, AU - Cole,Kelli, AU - Bogema,Marlee, AU - Duffner,Ulrich, AU - Williams,Stephanie, AU - Mageed,Aly, Y1 - 2015/03/09/ PY - 2015/01/12/received PY - 2015/02/09/accepted PY - 2015/3/14/entrez PY - 2015/3/15/pubmed PY - 2016/3/5/medline KW - Allogeneic blood and marrow transplantation KW - Bortezomib KW - Graft-versus-host disease prophylaxis KW - Post-transplantation cyclophosphamide SP - 1315 EP - 20 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol Blood Marrow Transplant VL - 21 IS - 7 N2 - 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. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/25765556/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(15)00115-9 DB - PRIME DP - Unbound Medicine ER -