Impact of genomic risk factors on outcome after hematopoietic stem cell transplantation for patients with chronic myeloid leukemia

Abstract

The online version of this article has a Supplementary Appendix. BackgroundNon-HLA gene polymorphisms have been shown to influence outcome after allogeneic hematopoietic stem cell transplantation. Results were derived from heterogeneous, small populations and their value remains a matter of debate. Design and MethodsIn this study, we assessed the effect of single nucleotide polymorphisms in genes for interleukin 1 receptor antagonist (IL1RN), interleukin 4 (IL4), interleukin 6 (IL6), interleukin 10 (IL10), interferon (IFNG), tumor necrosis factor (TNF) and the cell surface receptors tumor necrosis factor receptor II (TNFRSFIB), vitamin D receptor (VDR) and estrogen receptor alpha (ESR1) in a homogeneous cohort of 228 HLA identical sibling transplants for chronic myeloid leukemia. Three good predictors of overall survival, identified via statistical methods including Cox regression analysis, were investigated for their effects on transplant-related mortality and relapse. Predictive power was assessed after integration into the established European Group for Blood and Marrow Transplantation (EBMT) risk score. ResultsAbsence of patient TNFRSFIB 196R, absence of donor IL10 ATA/ACC and presence of donor IL1RN allele 2 genotypes were associated with increased transplantation-related mortality and decreased survival. Application of prediction error and concordance index statistics gave evidence that integration improved the EBMT risk score. ConclusionsNon-HLA genotypes were associated with survival after allogeneic hematopoietic stem cell transplantation. When three genetic polymorphisms were added into the EBMT risk model they improved the goodness of fit. Non-HLA genotyping could, therefore, be used to improve donor selection algorithms and risk assessment prior to allogeneic hematopoietic stem cell transplantation.

Analysis of non-HLA genomic risk factors in HLA-matched unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia

“…22 Xiao showed that even in heterogeneous related and unrelated donor cohorts, certain TGFB and IL10 polymorphisms (TGFB1-509T/T genotype, IL10 -1092, -819CC and -592 C/C genotypes) were associated with GVHD and survival. 23 The absence of the IL10 genotype (ATA/ACC) in the donors, as shown in our sibling CML cohort, 11 was associated with decreased survival and death in remission. Absence of the ATA haplotype in the donors was also associated with Genomic risk factors in HCT for CML haematologica | 2012; 97 (7) 1017 © F e r r a t a S t o r t i F o u n d a t i o n death in remission in an unrelated and sibling Chinese transplantation population.…”

“…10 In general, these studies were based on small series and the results were not adjusted for the key risk factors for HCT outcomes. The role of non-HLA genetics was previously studied in a homogenous cohort of 228, primarily Caucasian, adult CML patients with HLA-matched sibling donors, transplanted from 1984-2003; 11 the results were reported to the EBMT. Among nine targeted cytokines, cytokine receptors, or other genes of interest, an intronic variable number tandem repeat within the gene for interleukin 1 receptor antagonist (ILIRA), a single nucleotide polymorphism (SNP) within the tumor necrosis factor II receptor superfamily, member 1B (TNFRSF1B) gene, and the interleukin 10 (IL10) gene were associated with survival when analyzed alone and alongside the EBMT risk score.…”

Cytokine gene polymorphisms and graft-versus-host disease in children after matched sibling hematopoietic stem cell transplantation: a single-center experience

“…In a recent study of a homogenous cohort of 228 HLA-identical sibling transplants for chronic myeloid leukemia, the absence of donor IL-10 ATA/ACC was associated with increased TRM and decreased OS. 21 Regarding IL-10 production, it is still debatable whether the GCC haplotype is associated with higher or lower IL-10 production in comparison to the ATA haplotype. In another study of unrelated donor transplants, TRM was associated with the higher IL-10 producer GCC haplotype when present in the donor.…”

Predicting survival using clinical risk scores and non-HLA immunogenetics

“…To date, these studies with singlenucleotide polymorphisms (SNPs) have used small subsets of patients. [5][6][7][8][9] Although genome-wide association studies have been performed, 10 no SNP genotypes have been clearly identified so far that could be used to predict the outcome.…”