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Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation.
J Clin Oncol. 2012 Sep 10; 30(26):3202-8.JC

Abstract

PURPOSE

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.

PATIENTS AND 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.

CONCLUSION

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+Show Affiliations

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. jkoreth@partners.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

22869883

Citation

Koreth, John, et al. "Bortezomib-based Graft-versus-host Disease Prophylaxis in HLA-mismatched Unrelated Donor Transplantation." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 30, no. 26, 2012, pp. 3202-8.
Koreth J, Stevenson KE, Kim HT, et al. Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol. 2012;30(26):3202-8.
Koreth, J., Stevenson, K. E., Kim, H. T., McDonough, S. M., Bindra, B., Armand, P., Ho, V. T., Cutler, C., Blazar, B. R., Antin, J. H., Soiffer, R. J., Ritz, J., & Alyea, E. P. (2012). Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 30(26), 3202-8. https://doi.org/10.1200/JCO.2012.42.0984
Koreth J, et al. Bortezomib-based Graft-versus-host Disease Prophylaxis in HLA-mismatched Unrelated Donor Transplantation. J Clin Oncol. 2012 Sep 10;30(26):3202-8. PubMed PMID: 22869883.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. AU - Koreth,John, AU - Stevenson,Kristen E, AU - Kim,Haesook T, AU - McDonough,Sean M, AU - Bindra,Bhavjot, AU - Armand,Philippe, AU - Ho,Vincent T, AU - Cutler,Corey, AU - Blazar,Bruce R, AU - Antin,Joseph H, AU - Soiffer,Robert J, AU - Ritz,Jerome, AU - Alyea,Edwin P,3rd Y1 - 2012/08/06/ PY - 2012/8/8/entrez PY - 2012/8/8/pubmed PY - 2012/12/10/medline SP - 3202 EP - 8 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J Clin Oncol VL - 30 IS - 26 N2 - PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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. SN - 1527-7755 UR - https://www.unboundmedicine.com/medline/citation/22869883/Bortezomib_based_graft_versus_host_disease_prophylaxis_in_HLA_mismatched_unrelated_donor_transplantation_ L2 - https://ascopubs.org/doi/10.1200/JCO.2012.42.0984?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -