Donor Activating Kir Genes and Survival after Haplo-Identical Hematopoietic Transplantation.

Although NK cell alloreactivity impacts beneficially on the outcome of haploidentical transplantation in AML patients, largely through its GvL effect (Ruggeri et al, Science 2002), TRM (~40%, largely due to infections) remains a major problem. In a search for additional donor selection criteria, here we determined the donor KIR genotypes and correlated them with transplantation outcomes in 74 AML recipients. Transplants from donors carrying group A KIR haplotype genes, which mainly encode for inhibitory receptors (and for the activating KIR2DS4 gene) (n=22), were compared with those from donors carrying group B KIR haplotype genes, which encode for additional activating KIRs (KIR2DS1, 2, 3, 5 and KIR3DS1) (n=52). Event-free survival appeared better in AML patients transplanted from donors bearing B haplotype genes (48% vs 23%, p=0.066). As expected, other well established factors of good prognosis, such as NK cell alloreactivity and disease status at transplant, played significant independent roles (H.R.=0.42 donor NK cell alloreactivity present vs absent, 95% C.I.=0.22–0.79, p=0.007; H.R.=0.39 remission vs relapse at transplant, 95% C.I.=0.21–0.72, p=0.003). However, after adjusting for donor-vs-recipient NK cell alloreactivity and transplantation in remission, transplantation from donors carrying group B haplotype KIR genes still tended to emerged as an independent predictor of survival (H.R.=0.56 B haplotype genes present vs absent, 95% C.I.=0.3–1.0, p=0.07). This might have been the consequence of reduced incidence of leukaemia relapse. In an analysis of factors involved in relapse, donor-vs-recipient NK alloreactivity and disease status at transplant were confirmed as strong independent protective factors (H.R.=0.18 donor NK cell alloreactivity present vs absent, 95% C.I.=0.05–0.68, p=0.01; H.R.=0.15 remission vs relapse at transplant, 95% C.I.=0.04–0.58, p=0.006). Transplantation from donors carrying activating group B haplotype KIR genes had no effect on relapse (H.R.=0.59 B haplotype genes present vs absent, 95% C.I.= 0.17–2.05, p>0.1). Strikingly, in analyzing TRM, transplantation from these donors was associated with a markedly reduced TRM (59% vs 30%, p=0.03), and emerged as the only statistically significant protective factor (H.R.=0.46 B haplotype genes present vs absent, 95% C.I.= 0.22–0.97, p=0.04), even when compared with NK cell alloreactivity (H.R.=0.56 donor NK cell alloreactivity present vs absent, 95% C.I.=.026–1.20, p>0.1) and disease status at transplant (H.R.=0.53 remission vs relapse at transplant, 95% C.I.=0.25–1.11, p=0.09). Thus, transplantation from donors carrying activating (group B haplotype) genes could be a new donor selection criterion which might help reduce infectious mortality after haploidentical hematopoietic transplantation.

The mechanisms underlying this apparently improved immune competence remain to be investigated.