Impact of hereditary predisposition genes to hematologic malignancies on transplant outcomes and donor selection

Abstract Impact of Hereditary Predisposition Genes to Hematologic Malignancies on Transplant Outcomes and Donor Selection Background: With the advent of precision genomics, hereditary predisposition genes to hematologic malignancies have being increasingly recognized in clinical practice. Aim: In current study, the influence of hereditary predisposition genes related to hematologic and immune disorders on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and donor selection in patients with hematologic malignancies were studied. Methods: Between December 2017 and June 2024, 558 patients with hematologic malignancies who underwent allo-HSCT in our hospital were analyzed. The median age was 16.1 (0.3-71.4) years, with 260 (46.6%) adults and 298 (53.4%) children. Three hundred and twenty-nine (59.0%) patients were male. The diagnosis includedB-ALL(225, 40.3%), AML(157, 28.1%), T-ALL(37, 6.6%), T-LBL/ALL (33, 5.9% s), B-NHL(22, 3.9%), MDS(18, 3.2%) and others. Total 334 (59.9%) patients had relapsed before transplant, and 136 (24.4%) cases received the second allo-HSCT. Three hundred and eighteen (57.0%) patients achieved complete remission before transplant and 81 (14.5%) patients with concurrent central nervous system involvement. Donors were from haploidentical family members (391, 70.1%) or unrelated volunteers (125, 22.4%) or identical siblings (42, 7.5%). Myeloablative conditioning regimens with either total body irradiation/fludarabine-based or busulfan/fludarabine-based were applied. Anti-thymocyte globulin was used in haploidentical and unrelated transplants. Graft-versus-host disease prophylaxis was with cyclosporine, short-term methotrexate and mycophenolate mofetil. All patients were analyzed for hereditary predisposition gene variants before transplant. Genomic DNA was extracted from peripheral blood of patients, parents and other potential family donors, and tested using next generation sequencing. More than 700 hereditary predisposition genes were screened and analyzed. Results: Withthemedian follow-up 37.1 (95% CI: 31.6-39.8 months) months, 3-year overall survival (OS) was 66.3%, 3-years disease free survival was 59.2%,3-year cumulative incidence of relapse was 29.7%, and 3-year non-relapse mortality was 11.1%. Of 558 patients, 527 (94.4%) carried class I hereditary predisposition gene variants. Top 10 recurrent mutated genes were BTLA, TNFAIP3, MPEG1, EP300, MLH1, NCF2, MUTYH, KIT, STK11 and RET. Disease-specific enrichment mutated genes were DNMT3A in AML, UNC13D in MDS, IRF7 in B-ALL, and STK11and HAVCR2 in B-NHL. Age-stratified analysis revealed differential germline gene variant enrichment as pediatric-predominant at KIT, CARD14, PROC, and TLR1, and adult-predominant at ASXL1 and DNMT3A. Three hundred and seventy-two (66.7%) patients carried inborn errors of immunity (IEI)-associated class I gene mutations, the numbers of gene mutation category showed no significantly prognostic correlation. Forty-two (7.5%) patients harbored germline homozygous gene variants, with top recurrent mutated genesas WAS, BTLA, EP300, MPEG1, POLD1, STK11, TNFRSF13C, and UNC13D. Significantly improved transplant outcomes were noted in homozygous IEI gene variant carriers by unrelated donors compared with related donors. Three-year disease-free survival (DFS) was 87.5% vs. 40.0%, p =0 .0089, and 3-year OS was 87.5% vs. 58.3%, p =0 .00089. The IEI gene categories with the highest variant frequency were syndromic combined immunodeficiencies, defects in intrinsic and innate immunity, and bone marrow failure disorders. Germline gene variants in cellular and humoral immune deficiency emerged as independent risk factors for the outcomes post-HSCT. Compared with non-carriers, variant carriers had lower 3-year DFS(43.8% vs. 60.1%, p =0.026), and lower 3-year OS (46.5% vs. 67.3%, p = 0.021). Conclusions: Our study has showed the profile ofhereditary predisposition genes to hematologic malignancies. We have demonstrated that homozygous IEI gene variants resulted in inferior survival after allo-HSCT and the transplantation from unrelated donors could improve the outcomes remarkably. Germline gene variants in cellular and humoral immune deficiency are independent risk factors for poor transplant outcomes. These findings have indicated the significance of hereditary predisposition genes evaluation pre-transplant and appropriate donor selection.