Prognostic impact of donor KIR genotypes on clinical outcomes in pediatric allogeneic hematopoietic stem cell transplantation

Abstract Prognostic Impact of Donor KIR Genotypes on Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Background: Donor killer immunoglobulin-like receptor (KIR) genotypes critically modulate natural killer (NK) cell-mediated alloreactivity, potentially influencing outcomes after pediatric hematopoietic stem cell transplantation (HSCT). The precise clinical impact of donor KIR haplotypes, however, remains incompletely understood. This study aimed to elucidate associations between donor KIR genotypes and clinical outcomes following HSCT in pediatric patients with malignant hematologic disorders. Methods: We conducted a retrospective cohort study of 238 pediatric patients who underwent allogeneic HSCT for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS) between 2010 and 2023. Donor KIR genotypes were determined using PCR-based typing, classifying haplotypes as telomeric A/A (tAA) or telomeric B/x (tBx, containing ≥1 telomeric B gene). Activating KIR genes (KIR3DS1 and KIR2DS1) and donor–recipient KIR–HLA ligand mismatches (such as donor KIR3DL1 in the absence of recipient HLA-Bw4-80I ligand) were specifically assessed. Primary endpoints included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, non-relapse mortality (NRM), and acute/chronic graft-versus-host disease (GVHD). Statistical analysis employed Kaplan–Meier survival estimates with log-rank tests, cumulative incidence comparisons using Gray's test, and multivariate Cox regression models for confounder adjustments. Results: Of 238 donor–recipient pairs analyzed, 39% were tBx haplotype and 61% were tAA haplotype donors. Recipients of grafts from donors with tBx haplotypes exhibited significantly inferior outcomes compared with those receiving tAA haplotype grafts, including lower 3-year OS (59% vs. 73%, P=0.031) and DFS (53% vs. 68%, P=0.009). These results primarily stemmed from an elevated 3-year cumulative incidence of relapse (24% vs. 10%, P=0.004) and increased relapse-related mortality (19% vs. 8%, P=0.019). Additionally, the absence of either activating KIR gene (KIR2DS1 or KIR3DS1) among tBx donors further increased the relapse rate (30% vs. 15%, P=0.004) and NRM (30% vs. 21%, P=0.0025) compared to donors possessing both activating genes. In the ALL subgroup achieving complete remission prior to HSCT, concurrent donor–recipient lack of HLA-Bw4-80I ligand correlated with significantly poorer outcomes when donors expressed KIR3DL1 (3-year OS: 65% vs. 88%, P=0.012; DFS: 60% vs. 80%, P=0.038), indicating compromised NK cell education. Subgroup analyses underscored the detrimental impact of donor tBx haplotypes particularly in haploidentical HSCT settings, manifesting in higher relapse rates relative to tAA donors (30% vs. 12%, P=0.028). Importantly, rates of acute and chronic GVHD were comparable between donor haplotype groups. Conclusions: Our findings establish a significant association between donor KIR genotypes and clinical outcomes post-HSCT in pediatric patients with hematologic malignancies. Telomeric B haplotypes, especially when lacking activating KIR genes (KIR2DS1 and KIR3DS1), predict higher relapse rates and reduced survival, notably in haploidentical HSCT and HLA-KIR mismatch scenarios. These data advocate for integrating KIR genotype analysis into donor selection algorithms to enhance clinical outcomes in pediatric allogeneic HSCT.