Prognostic Significance of Interleukin-7 Receptor-Alpha Gene Polymorphisms in Allogeneic Stem Cell Transplantation: a Confirmatory Study.
Authors: Shamim Zaiba , Ryder Lars Peter , Christensen Ib Jarle , Toubert Antoine , Dickinson Anne M. , Müller Klaus 
Published: October 2019

Abstract
Abstract 798
Interleukin-7 (IL-7) belongs to the hematopoietic family of cytokines, being essential for T cell development in the thymus and maintenance of peripheral T cells. IL-7 signals through IL-7R, which consists of the gamma common chain as well as an alpha-chain. The alpha-chain, is also used by the receptor of thymic stromal–derived lymphopoitin (TSLP), a cytokine with complex effects on cytokine profiles, including induction of TNF production by dendritic cells. We have sequenced IL-7Ralpha and identified the existence of 4 single nucleotide polymorphisms (+510C/T, +1237 A/G, +2087T/C and +3110A/G), that all give rise to amino acid substitutions. In a previously published study, we found that the G allele of the +1237 SNP of the donor was associated with increased overall mortality and treatment related mortality in patients having matched unrelated donors (MUD) SCT. The aim of the present investigation was to validate these findings in a study of a British-French cohort of SCT patients.

Patients and methods:
IL-7Ralpha polymorphisms were determined by a SSP-PCR system in genomic DNA from 119 transplants with either matched sibling donors (n=93) or MUD (n=26). The indication for SCT included AML (n=32), CML (n=27), ALL (n=18), other malignancies (n=29) and benignant haematological disorders (n=11).

Results:
Donor homozygozity for the T allele at position +510 was associated with increased overall mortality (HR:1.99 (95%CI:1.03-3.84) p=0.04) as well as treatment related mortality (TRM) (HR: 1.38 (95% CI:1.38-6.03) p=0.0054), as evaluated by multivariate testing using Cox regression analysis. In contrast, this SNP was unrelated to the risk of relapse. A similar pattern was found for the +1237 SNP, with increased TRM associated with homozygozity for the G allele in the donor (HR: 2.28 (95%CI:1.09-4.77) p=0.03) , although the association between this genotype and overall mortality was not significant (HR: 1.72 (95%CI:0.90-3.26) p=0.10).
In line with this, the frequency of grade 3-4 acute GvHD was related to the +510 genotype of the donor: (TT (50%), CT (8%), and CC (15%) (OR=7.70 (95%CI:2.47-24), p= 0.0004) as was the +1237 SNP: GG (43%), AG (6%) and AA (16%) (OR=6.26 (95%CI:2.06-19), p=0.001) (multivariate analysis).
There was no clear association between the recipient genotype of these IL-7Ralpha SNPs or with the +2087 or +3110 SNPs.

Conclusion:
The presented data confirms our previous finding that the +1237 genotype of the donor is related to TRM and acute GvHD after SCT. Moreover, the data suggests a similar pattern for the +510 SNP of the donor, in line with the fact that +510 and +1237 SNPs are in close linkage disequlibrium. These findings suggest that IL-7 and/or TSLP pathways may be of pathogenetic importance for transplant related mortality and acute GvHD, and suggest that modulation of these pathways may have an impact on the outcome in SCT. Finally, the study suggests that selection of donors based on IL-7Ralpha typing, in addition to HLA typing, may help to improve the outcome in SCT.

Disclosures:
No relevant conflicts of interest to declare.