Abstract
BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Disease relapse remains a major cause of transplant failure. T cell homeostasis is critical to determine the potency of the GVT effect. Recent studies have shown the association of the CTLA-4 polymorphisms with the outcome after HLA-identical sibling allogeneic HSCT.MethodsIn this study, we focused on four CTLA-4 polymorphisms, and analyzed the impact of donor genotypes and haplotypes on the conditions of 152 acute leukemia patients (ALL 83) after related HLA-haplotype- mismatched transplantation. The four SNP genotypes (−1661, −318, CT60 and +49) were determined by TaqMan SNP genotyping assays.ResultsALL recipients of donors with +49 GG showed significantly lower OS (67.7 vs. 90.3 %, P = 0.015) than those with GA+AA. Multivariate analyses showed that +49 GG was an independent risk factor for OS (HR: 0.306, 95 % CI 0.111–0.842, P = 0.022) .23 ALL patients receiving mDLI showed significantly lower OS with +49 GG donor than those with GA+AA (30.0 vs. 83.1 %, P = 0.003). The haplotype analysis revealed only three haplotypes in the donor population −1661/−318/CT60/+49 i.e., ACGG, ACAA and GTGA, the frequencies were 64.1, 19.4 and 16.5 %, respectively. Donors with and without the ACGG/ACGG haplotype had the same effect on transplant outcomes as those with +49 GG and +49 GA+AA.ConclusionIn summary, the CTLA-4 +49 GG and the haplotype ACGG/ACGG reduced the overall survival in ALL after allo-HSCT from the related HLA-haplotype-mismatched donor, knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for donor selection and individual application of immunosuppressive agents and immunotherapy.
Highlights
Allogeneic hematopoietic stem cell transplantation has been established as an effective treatment for patients with hematological malignancies
We focused on these four CTLA-4 polymorphisms and analyzed the impact of donor genotypes and haplotypes in 152 acute leukemia (ALL 83) patients on the outcomes after related human leukocyte antigen (HLA)-haplotype-mismatched transplantation
In this study, we focused on the four CTLA-4 SNP polymorphisms and analyzed the impact of donor genotypes and haplotypes on the outcome in AL patients after related HLA-haplotype-mismatched transplantation
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as an effective treatment. CTLA-4 is a receptor expressed on the activated T cell surface and is a homolog of CD28 that is responsible for T cell activation. Recent studies have shown the association of the CTLA-4 polymorphisms [−1661 (rs4553808), −318 (rs5742909), +49 (rs231775), and CT60 (rs3087243)] with the outcome after HLA-identical sibling allogeneic HSCT [10,11,12]. We focused on these four CTLA-4 polymorphisms and analyzed the impact of donor genotypes and haplotypes in 152 acute leukemia (ALL 83) patients on the outcomes after related HLA-haplotype-mismatched transplantation
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