Donor Genetic Determinant of Thymopoiesis rs2204985 Impacts Clinical Outcome after Single HLA Mismatched HSCT

Introduction: A common genetic variant within the TCRA-TCRD locus has been recently identified as a predictive factor of thymic function and T cell repertoire diversity (Clave et al., 2018). Specifically it was shown in a mouse model that transplantation of rs2204985 AA human hematopoietic stem cells (HSC) into immunodeficient mice led to lower thymocyte counts and poorer TCR diversity. T cell mediated pathways are known to play a significant role in immunological processes affecting HSCT outcome like GvL, GvH and infection. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated HSCT.

Methods: The study included 2,016 adult patients with hematologic malignancies who received their first unrelated (10/10 or 9/10 HLA matched) graft between 2000 and 2013 in a German transplant center. Patients with refractory disease at time of transplantation were excluded from the analysis. Both donors and patients were retrospectively genotyped for the TCRA-TCRD rs2204985 polymorphism by next generation sequencing using a validated protocol on an Illumina Miseq platform. Overall survival (OS), disease free survival (DFS), relapse (RI), non-relapse mortality (NRM), acute GvHD (aGvHD) and chronic GvHD (cGvHD) were evaluated; p<0.05 was considered significant and donor rs2204985 GG/AG genotype was set as reference vs the AA genotype. Stratification for diagnosis was performed and a backward stepwise model finding approach was used to select variables related to a given outcome with a threshold of 0.10 for retention in the model.

Results: The rs2204985 genotype frequencies found in both patients and donors were in line with those previously reported for Caucasian populations indicating a codominance of the two alleles (i.e. A and G). Regarding the impact of this genetic variation on outcome, multivariate analysis of the combined cohort indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations, therefore subanalysis on account of HLA incompatibility was performed. Analysis in the subgroup of single HLA mismatched cases (n=624) revealed that donor AA genotype associated with markedly inferior OS (55.1% vs 70.6%, p=0.004, Fig. 1) and DFS (47.6% vs 63.4%, p=0.002, Fig. 2) one year after HSCT as compared to the donor AG/GG genotypes. These results were confirmed in the corresponding multivariate models (OS HR: 1.48, p=0.003; DFS HR: 1.50, p=0.001) which are visually displayed as forest plots in Fig. 3 and Fig 4, respectively. The adverse effect of donor AA genotype on survival appears to be driven by a combined higher risk of RI (1Y after HSCT: 29.3% vs 18.3%, p=0.048; HR: 1.38, p=0.035) and NRM (1Y after HSCT: 28.6% vs 19.9%, p=0.043; HR: 1.38, p=0.042) as shown by both the univariate and multivariate analyses for the two respective endpoints. No association was found between donor rs2204985 genotype and risk of acute or chronic GvHD. The donor rs2204985 genotype had also no significant impact on any outcome endpoint in the 10/10 HLA matched subgroup. Last, no significant interactions were observed between this variable and the other adjusted covariates in the multivariate models.

Conclusion: To our knowledge this is the first study to date investigating the potential effect of donor's genotype regarding a common genetic variant within the TCRA-TCRD locus on the outcome of patients receiving unrelated HSC grafts. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely affect the outcome of HSC transplanted patients and should therefore be avoided. It is of note that one in four unrelated donors of Caucasian origin is expected to carry the AA genotype. A weaker relapse and -presumably- infection control, especially in the early post-transplantation period, due to compromised T cell reconstitution as a result of the unfavorable donor AA genotype may account for these findings. Confirmatory studies in larger independent cohorts are warranted before final conclusions are drawn.

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