NK Alloreactivity Evaluation According to KIR‐HLA Interaction Models Influences the Outcome of Haploidentical Haematopoietic Stem‐Cell Transplantation Based on Post‐Transplant Cyclophosphamide

ABSTRACT Haploidentical haematopoietic stem‐cell transplantation (haplo‐HSCT) is characterised by a high degree of HLA mismatching. Therefore, NK alloreactivity driven by the interactions between KIR and HLA mismatched molecules could benefit its outcome. However, the influence of NK alloreactivity in haplo‐HSCT with post‐transplant Cyclophosphamide (PTCy) remains controversial. The aim of this work was to investigate the clinical utility of predicting NK alloreactivity according to previously described models in the context of haplo‐HSCT with PTCy. We studied 145 patients who underwent this procedure, evaluating the influence of NK alloreactivity in transplant outcomes. Models that disregard the interactions between KIR and HLA evidenced an unsuccessful prediction of the outcomes. On the contrary, approaches based on KIR‐HLA interaction were the most accurate to predict transplant outcomes. The analysis of inhibitory KIRs (iKIRs) based on the missing‐ligand model showed that the presence of at least two iKIR mismatches (iKIRmm) among the donor‐recipient pair was an independent risk factor for acute graft‐versus‐host disease (aGvHD) grade III‑IV (HR: 3.21, p = 0.021), relapse rate (HR: 2.46, p = 0.046), relapse‐free survival (RFS) (HR: 1.96, p = 0.039) and GvHD/relapse‐free survival (GRFS) (HR = 2.16, p = 0.008). The analysis of the missing‐licensing model showed that the existence of the mismatch KIR2DL1/C2 associated to relapse rate (HR: 4.34, p = 0.002) and more than one iKIRmm correlated to poorer RFS (HR: 2.31, p = 0.038) and GRFS (HR: 2.26, p = 0.022). These results suggest that NK alloreactivity influences the outcome of haplo‐HSCT with PTCy and should be incorporated into the donor selection algorithm for this procedure.