The Presence and Number of Activatory KIR (R+D−) Impact the Infection and Survival Status of Patients Transplanted with an HLA Matched Sibling Donor.

Killer immunoglobulin-like receptor (KIR) ligand incompatibilities (=absence on recipient tissues of a ligand for KIRs present in the graft) have been associated with decreased relapse, rejection and acute GVHD, after T cell depleted haplo and unrelated donor Hematopoietic Stem cell transplantation, mainly for myeloid hematopoietic malignancies. The association of donor and recipient KIR genotypes with outcomes, including infections, after HLA genoidentical HSCT has not been studied. We have analysed genotypes for ten KIR genes (2DS1, 2DS2, 2DS3, 2DS4, 2DL1, 2DL2, 2DL3, 3DS1, 3DL1, 3DL2) in 131 donor-recipient pairs from HLA-matched sibling bone marrow transplantations performed for lymphoid (53 cases) and for myeloid malignant diseases (78 cases). We classified the pairs according to KIR-ligand incompatibilities and donor-recipient KIR matching (=concommitant expression of KIRs in donors and recipients). Median age was 29 years. 105 patients were transplanted for a low risk disease, 12 for intermdiate and 14 for high risk disease. Conditioning was myeloablative in all cases and consisted in TBI based (n=63). Cyclosporine and Methotrexate for GVHD prophylaxis was used in 118 cases. Cumulative incidence (competing rsik analysis) of acute GVHD at day 100 and CI of 180 days-bacterial, CMV and fungal infections were 48%, 19%, 34%, 11%, respectively. 5 years overall survival was 70%. We have not found any significant association of “KIR-ligand incompatibilities”, donor KIR genotype, number of activatory KIR genes present in the donor and donor-recipient matching for each KIR with aGVHD, relapse, bacterial, viral or fungal infection and survival, except for KIR2DS2. In fact, donor-recipient mismatching for KIR2DS2 was associated with the incidence of acute GVHD (II-IV p=0.05). Although not significant, we have also observed a trend with decreased survival in patients homozygous for group 2 HLA-C and grafted for myeloid malignant disease with a HLA-matched sibling donor carrying the activatory KIR2DS2 (63 % survival at 20 months (N=6) versus 86% (N=9)). Finally,. the higher is the number of activatory KIRs present in the recipient (R+) and absent from the donor (D−), the higher is the risk of fungal (p=0.03) and CMV infection (p=0.05) and the worse is the survival (at 5 years: 78% survival in case of 0 KIR R+D−, 64% in case of 1 or 2 KIR R+D− and 44% in case of 3 or 4 KIR R+D−, p=0.001). A multivariate analysis for survival confirmed the association of number of R+D− activatory KIR (p = 0.001, HR = 3.13) among other clinical factors such as gender (p=0.03), ABO compatibility (p=0.003), recipient age (p=0.01) and status of the disease (p = 0.0001).