Haploidentical hematopoietic transplantation from KIR ligand–mismatched donors with activating KIRs reduces nonrelapse mortality

Abstract

Key Points• Haploidentical transplantation from KIR ligand-mismatched donors with activating KIRs reduces nonrelapse mortality and improves survival.• Activating KIR genetics should be considered when selecting donors for T cell-depleted haploidentical hematopoietic transplantation.Because activating killer cell immunoglobulinlike receptors (KIRs) are heterogeneously expressed in the population, we investigated the role of donor activating KIRs in haploidentical hematopoietic transplants for acute leukemia. Transplants were grouped according to presence vs absence of KIR-ligand mismatches in the graft-vs-host direction (ie, of donorvs-recipient natural killer [NK]-cell alloreactivity). In the absence of donor-vs-recipient NK-cell alloreactivity, donor activating KIRs had no effects on outcomes. In the 69 transplant pairs with donor-vs-recipient NK-cell alloreactivity, transplantation from donors with KIR2DS1 and/or KIR3DS1 was associated with reduced risk of nonrelapse mortality, largely infection related (KIR2DS1 present vs absent: hazard ratio [HR], 0.25; P 5 .01; KIR3DS1 present vs absent: HR, 0.18; P 5 .006), and better event-free survival (KIR2DS1 present vs absent: HR, 0.31; P 5 .011; KIR3DS1 present vs absent: HR, 0.30; P 5 .008). Transplantation from donors with KIR2DS1 and/or KIR3DS1 was also associated with a 50% reduction in infection rate (P 5 .003). In vitro analyses showed that KIR2DS1 binding to its HLA-C2 ligand upregulated inflammatory cytokine production by alloreactive NK cells in response to infectious challenges. Because ∼40% of donors able to exert donor-vs-recipient NK-cell alloreactivity carry KIR2DS1 and/or KIR3DS1, searching for them may become a feasible, additional criterion in donor selection. (Blood. 2015;125(20):3173-3182)

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion

“…Also donor-derived, mature NK cells, lost in the procedure of positive selection of CD34 1 cells and spared in our ab T-cell-depleted graft, exhibit a graft-versus-leukemia (GVL) effect 6,10,[14][15][16]41,42 and participate in the control of opportunistic infections, including HCMV. [43][44][45] In previous studies, we documented that in haplo-HSCT recipients given positively selected CD34 1 cells, ;8 weeks after transplantation are needed to detect mature KIR 1 NK cells, and this gap in reconstitution may favor early leukemia relapse in the case of high residual tumor burden and/or rapidly proliferating blasts. 14,16 Through the approach of selective ab T-and B-cell depletion, the recipient immediately benefits from high numbers of donor mature NK cells that can fully display their activity, because the recipient is not exposed to the effect of pharmacological prophylaxis of GVHD, which can impair differentiation/expansion of this lymphocyte subset.…”

How to select the best available related or unrelated donor of hematopoietic stem cells?

“…by identifying the presence of the KIR2DS1 locus 58 or by identifying KIR B haplotype-positive donors. 59,60 An even more sophisticated approach would take into account the KIR2DL1 allelic polymorphism affecting the strength of the inhibitory receptor.…”

Donor Natural Killer Cells and Their Therapeutic Potential in Allogeneic Hematopoietic Stem Cell Transplantation

“…In addition, KIR3DS1 was also found to associate with lower rate of relapse and infection. Mancusi A et al reported KIR3DS1 was associated with reduced infection mortality [115]. Further studies are still needed to identify ligands for activating KIR so as to confirm the effect of each activating KIR gene on allo-HSCT outcome.…”