Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for a wide range of hematologic disorders; however, graft failure and graft-versus-host disease (GVHD) remain major determinants of transplant-related morbidity and mortality. While donor–recipient HLA matching is central to transplant success, the contribution of non-HLA genomic factors to engraftment and GVHD risk is not fully defined. Methods We conducted a retrospective, population-based cohort study including 312 adult patients who underwent first allo-HSCT at Danish transplantation centers between 2010 and 2023. Donor and recipient genomic data were analyzed using targeted next-generation sequencing focusing on immune regulatory and stem cell homing–related genes. Primary outcomes were neutrophil engraftment and acute GVHD, with overall survival as a secondary endpoint. Associations between genomic variants and transplant outcomes were evaluated using Kaplan–Meier analysis, competing-risk models, and multivariable Cox regression. Results Neutrophil engraftment was achieved in 95.2% of patients at a median of 17 days. Polymorphisms in the CXCL12 pathway were associated with delayed engraftment (median 20 vs 16 days; P = 0.004) and increased graft failure. Acute GVHD of grade II–IV occurred in 27.9% of patients and was significantly associated with variants in IL6, TNF, and NOD2/CARD15. Patients harboring ≥2 high-risk genomic variants exhibited inferior 3-year overall survival (44.1% vs 66.4%; log-rank P < 0.001). Genomic risk remained independently associated with GVHD and survival after adjustment for clinical and transplant-related factors. Conclusions Non-HLA genomic variation significantly influences engraftment kinetics, GVHD development, and survival following allo-HSCT in a Danish cohort. Incorporation of targeted genomic profiling into pre-transplant risk assessment may enhance personalized transplant strategies and improve clinical outcomes.

Allogeneic stem cell transplantation; Genomics; Graft-versus-host disease; Engraftment; Precision medicine