Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is a critical T cell molecule that inhibits T cell activation and plays an essential role in T cell homeostasis and immune responses. Genetic variations in the CTLA4 gene have been hypothesized to be possible biologic markers that are predictive of transplant outcomes. Previous investigators have studied single nucleotide polymorphisms (SNPs) of the CTLA4 gene and its impact on hematopoietic cell transplantation (HCT) outcomes with discordant results. AA and AG genotypes in the donor CTLA4 regulatory region involving SNP rs4553808 in patients after unrelated donor (URD) HCT have recently been shown to be an independent predictor of improved relapse free survival (RFS) and overall survival (OS) compared to the GG genotype. To validate these preliminary findings, a Center for International Blood and Marrow Research (CIBMTR) study was performed in a larger, more homogenous cohort of patients.

Adult patients with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS) undergoing a first 8/8 or 7/8 HLA matched URD HCT after myeloablative, non-myeloablative, or reduced intensity conditioning from 2002 to 2007 in first or second complete remission with available donor research samples from the National Marrow Donor Program research repository were included. The primary goal was to evaluate the impact of SNP rs4553808 on RFS, OS, and NRM and the cumulative incidence of acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Any GVHD prophylaxis could be used except in vitro T-cell depletion or use of in vivo/in vitro alemtuzumab. Patients receiving T cell depletion with anti-thymocyte globulin (ATG) were oversampled to allow analysis of any effects on outcomes. An exploratory analysis of 9 other tagSNPs that encompass the entire CTLA4 gene (rs231775, rs231779, rs11571315, rs231777, rs3087243, rs16840252, rs231725, rs10197010, rs11571316) was performed to evaluate for any additional potential associations with clinical outcomes.

Each SNP was analyzed in multivariable models adjusting for clinically significant variables using the Cox proportional hazards model. Due to multiple testing, p-values <0.005 were considered significant. The interaction with CTLA4 SNPs and use of ATG was also specifically analyzed. The final analysis included 780 patients with a median followup of 63 months. Median age of recipients and donors was 50 and 34, respectively. 90% of recipients were identified to be of Caucasian descent (N=709). 80% of patients had AML (N=624) and 20% MDS (N=156). Conditioning was 61% ablative, 28% reduced intensity and 11% non-myeloablative, with 74% receiving peripheral blood grafts. 75% were HLA-matched and 25% single locus mismatched. Tacrolimus with methotrexate or mycophenolate mofetil GVHD prophylaxis was given to 62%, cyclosporine-based prophylaxis to 15% while 23% received other regimens. By design, 50% of patients received ATG. Genotyping showed that 552 (71%) were AA, 208 (27%) were AG and 19 (2%) were GG (AG, and particularly GG, were associated with worse outcomes in the prior study). Multivariable analysis adjusting for significant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS (p=0.07), RFS (p=0.41), NRM (p=0.25), and incidence of acute and chronic GVHD (Figure 1). Multivariable analysis of the other 9 tagSNPs also showed no association with transplant outcomes (p>0.005). No interaction was found between the CTLA4 SNPs and use of ATG on outcomes. These results indicate that CTLA4 SNPS do not have impact on outcomes. Other genomic or cellular biomarkers need to be studied to risk stratify patients at high risk of negative clinical events, especially as therapies targeting CTLA4 and PD-1 evolves.
Figure 1
Figure 1. (A) adjusted cumulative incidence of grades 2-4 aGVHD, (B) adjusted probability of overall survival, (C) adjusted cumulative incidence of non-relapse mortality, (D) adjusted probability of relapse free survival stratified by donor CTLA4 SNP rs4553808 genotype.
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(A) adjusted cumulative incidence of grades 2-4 aGVHD, (B) adjusted probability of overall survival, (C) adjusted cumulative incidence of non-relapse mortality, (D) adjusted probability of relapse free survival stratified by donor CTLA4 SNP rs4553808 genotype.

Figure 1
Figure 1. (A) adjusted cumulative incidence of grades 2-4 aGVHD, (B) adjusted probability of overall survival, (C) adjusted cumulative incidence of non-relapse mortality, (D) adjusted probability of relapse free survival stratified by donor CTLA4 SNP rs4553808 genotype.
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(A) adjusted cumulative incidence of grades 2-4 aGVHD, (B) adjusted probability of overall survival, (C) adjusted cumulative incidence of non-relapse mortality, (D) adjusted probability of relapse free survival stratified by donor CTLA4 SNP rs4553808 genotype.

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
antigens, donors, single nucleotide polymorphism, t-lymphocytes, cytotoxic, transplantation, graft-versus-host disease, chronic, biological markers, graft-versus-host disease, human leukocyte antigens, alemtuzumab

Author notes

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Asterisk with author names denotes non-ASH members.

© 2013 by The American Society of Hematology
2013
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