Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia

Abstract

Killer-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system. Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs. Aiming to develop a donor selection strategy to improve transplant outcome, we compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors. We KIR genotyped donors from 1409 unrelated transplants for acute myelogenous leukemia (AML; n = 1086) and acute lymphoblastic leukemia (ALL; n = 323). Donor KIR genotype influenced transplantation outcome for AML but not ALL. Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect. With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4% compared with 36.5% for Cen-A/A donors (relative risk of relapse 0.34; 95% confidence interval 0.2-0.57; P < .001). Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (relative risk 0.64; 95% confidence interval 0.48-0.86; P = .003) for both HLA-matched and mismatched transplants. KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content. Adopting this practice could result in superior disease-free survival for patients with AML.

Figure 1

The KIR locus comprises centromeric (Cen) and telomeric (Tel) gene content motifs. (A) The organization of genes in the KIR locus. The centromeric and telomeric regions are separated by a unique recombination site (RS) sequence that can function to reassort the centromeric and telomeric gene motifs. The gene content of the common motifs is shown. The conserved framework genes are shaded gray, B haplotype genes are blue, and A haplotype genes are red. (B) Groups used for the Cen and Tel analysis on the basis of the content of the inhibitory (L-long) or activating (S-short) KIR genes, and their frequencies among donors in the AML and ALL cohorts. (C) KIR B–content score and the frequency of donors in each group. The KIR B–content score is calculated by adding the number of Cen-B and/or Tel-B motifs in each genotype.

Figure 2

Specific reduction in relapse and improvement in DFS from donors with Cen-B/B after transplantation for AML but not ALL. Donors were assigned Cen-A/A, Cen-A/B, and Cen-B/B genotypes. Top, the incidence of relapse (A) and probability of DFS (B) for AML patients. Bottom, the incidence of relapse (C) and probability of DFS (D) are shown for ALL patients on the basis of their donor Cen genotype group.

Figure 3

Donors with Tel-B/B contribute to reduction in relapse after transplantation for AML. Donors were assigned Tel-A/A, Tel-A/B, and Tel-B/B genotypes. The incidence of relapse is shown for the respective groups.

Figure 4

Protection against relapse and improved DFS on the basis of donor KIR B–content groups in AML. The AML cohort was evaluated for relapse (A) and DFS (B) on the basis of donor KIR B content by use of the indicated groups. On the basis of this analysis, donor KIR B–content groups are divided as: (1) “best” with a KIR B–content score of more than 2 where the KIR haplotype is Cen-B/B, Tel-x/x (defined as 2DL3 absent, 2DS2 and/or 2DL2 present); (2) “better” with a KIR B–content score of more than 2 and the KIR haplotype is Cen-A/x, Tel-B/x (defined as 2DL3 present, 2DS2 and/or 2DL2 present, 3DS1 and/or 2DS1 present or 2DL3 present, 2DS2 and/or 2DL2 absent, and 3DS1 and/or 2DS1 present); or (3) “neutral” with a KIR B–content score of 0 or 1 (defined as 2DL3 present, 2DS2 and/or 2DL2 absent, 3DL1 and 2DS4 present).

Figure 5

Selection of donors with KIR B–content scores of 2 of greater has significant potential to improve the outcome of HLA-matched and HLA-mismatched HCT. For patients transplanted for AML, the incidence of relapse (A-B), the probability of DFS (C-D) and the probability of overall survival (E-F) are shown. Panels A, C, and E show the data from HLA-matched transplants, and panels B, D, and F show the data from HLA-mismatched transplants. Comparison is made between donors with a KIR B–content score of 0 or 1 (374 matched and 374 mismatched) and donors with a KIR B–content score of 2 or greater (162 matched and 165 mismatched).