Donor's Genetic Variability in NFAT5 and ATBF1, Transcriptional Factors Involved in Cellular Growth and Proliferation, Are Prognostic Factors for Disease Free Survival After Allogeneic Stem Cell Transplantation (Allo-SCT).

Abstract 2446

Poster Board II-423

Donor's hemopoietic progenitor cells leads to myeloid and lymphoid engraftment in the recipient, which is followed not only by a hematological recovery but also by crucial immune and inflammatory reactions. Many studies have focused their interest in the role of donor's genetic characteristics involved in immune responses after allo-SCT. However, very few of them have analysed genes that modulate the intensity of inflammatory response. We have studied the potential influence of polymorphisms in donor's genes involved in TGF-β signalling pathway and in cell growth and proliferation on clinical outcomes after allo-SCT, specifically on the incidence of acute GVHD (aGVHD), transplant related mortality (TRM), relapse, and disease free survival (DFS). The study population consisted of 106 donor-patient pairs undergoing HLA identical sibling allo-SCT in a single institution. Patient median age was 38 years (range, 5-66), and 44% were females. All patients were diagnosed with hematological malignancies; 52% of them were in advanced phase at transplantation. 29% of the patients received a reduced intensity conditioning. Mobilized peripheral blood progenitor cells were the source of hemopoietic stem cells in 98% of the cases. Donor's DNA was genotyped by allelic discrimination PCR for 15 single nucleotide polymorphisms (SNPs) in genes related to TGF-β signaling pathway (SMAD3, EP300, TGFB1, FURIN, PRF1, FNBP3) and in genes involved in regulation of cell growth and proliferation (ATBF1, NFAT5, NM1, CD151, TCIRG1, SH3KBP1, AKT2). Cumulative incidence for aGVHD, TRM and relapse was computed with the cmprsk package for R 2.6.2 software. Competing events were death in the case of aGVHD and relapse, and relapse in the case of TRM. Univariate and multivariate analysis for DFS was performed with actuarial probabilities using Kaplan-Meier with log-rank test and with Cox regression including in the model phase of disease. Multivariate analysis of TRM and relapse was performed using the regression model of Fine and Gray with the cmprsk package. None of the different genotypes analyzed had an association with the incidence of aGVHD. In contrast, different genotypes in NFAT5 and ATBF1 were associated with the incidence of TRM and relapse, respectively. Donor NFAT5 rs6499244 AA dominant genotype was associated with a higher incidence of TRM (p=0.001). At multivariate analysis, this genotype was the most important factor for TRM (RR 3.7, p=0.003). Donor ATBF1 rs719327 AA dominant genotype was associated with a higher incidence of relapse (p=0.03). At multivariate analysis, this genotype retained its significance (RR 1.8, p=0.03). Finally, both SNPs had an association with DFS, showing in the multivariate analysis NFAT5 AA dominant genotype and ATBF1 AA dominant genotype a lower DFS after allo-SCT (RR 1.8, p=0.025 and RR 1.7, p=0.035; respectively). Of them, NFAT5 AA dominant genotype was the most important prognostic factor for DFS. NFAT5 is necessary for optimal T cell development in vivo and ATBF1 inhibits cell proliferation acting as a tumor suppressor gene. In conclusion, donor's genetic variants in NFAT5 and ATBF1 have a strong influence on the clinical outcome of allo-SCT. If confirmed in other series, carrying these SNPs in these genes might be important in donor selection criteria.