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Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies.

ABSTRACT: Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41-0.89; P?=?0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27-0.86, P?=?0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47-0.99; P?=?0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35-1.06; P?=?0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT.

SUBMITTER: Espinoza LJ

PROVIDER: S-EPMC3160316 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies.

Espinoza Luis J LJ Takami Akiyoshi A Nakata Katsuya K Yamada Kayoko K Onizuka Makoto M Kawase Takakazu T Sao Hiroshi H Akiyama Hideki H Miyamura Koichi K Okamoto Shinichiro S Inoue Masami M Fukuda Takahiro T Morishima Yasuo Y Kodera Yoshihisa Y Nakao Shinji S

PloS one 20110823 8

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recip ...[more]

PMID: 21886827

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Project description:PurposeHematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT.Patients and methodsWe performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy.ResultsNotably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS.ConclusionOur prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

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Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies.

Publications

Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies.

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