Donor KIR3DL1 and HLA-B Allotypes Control Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Giglio Fabio , Gooley Ted A. , Venstrom Jeffrey M , Gallagher Meighan M , Hou LiHua , Hurley Carolyn K , Lebedeva Tatiana , Noreen Harriet , Rajalingam Raja , Reed Elaine F , Yu Neng , Vierra-Green Cynthia , Haagenson Michael D , Malkki Mari , Petersdorf Effie W. , Spellman Stephen , Hsu Katharine C. 
Published: October 2019

Abstract
Abstract 349
Natural killer (NK) cells are vital in the control of viral infection and malignancy, in particular AML. Affinity strength between NK receptors and their HLA ligands control both NK effector function and degree of NK inhibition. Differences in binding affinity between allotypes of the NK receptor KIR3DL1 and allotypes of its ligand HLA-Bw4 depend on the expression levels of the receptor and the amino acid residue at position 80 in the ligand. Because receptor-ligand affinities are associated with differences in HIV control, we hypothesized that different affinities between donor KIR3DL1 and donor-recipient HLA-Bw4 allotypes would impact the risk for AML relapse following allogeneic hematopoietic stem cell transplantation (HCT).

Methods:
We evaluated 299 AML patients who underwent allogeneic HCT from an unrelated donor between 1995 and 2002. Clinical data, HLA allotyping, and donor DNA were provided by the CIBMTR. KIR3DL1 allotyping was executed using PCR- and sequence-based methods. Donors were segregated into those with high-, low- and null expressing KIR3DL1 allele groups [3DL1-H (n=130), 3DL1-L (n=69), 3DL1-N (n=82)] and HLA-B allele groups (Bw6/Bw6, Bw4-I80, Bw4-T80). 3DL1-N genotypes are predictive of poor surface expression and were analyzed separately. Patients and donors were matched at 9 or 10 HLA loci in all cases, with only 3 donor-patient pairs mismatched for HLA-Bw4 ligands. Affinity cohorts were compared using Cox regression for the time-to-event outcomes of relapse and overall mortality (OM). Kaplan-Meier estimates of overall survival and cumulative incidence estimates of relapse were obtained.

Results:
Recipients of 3DL1-H and 3DL1-L donors were analyzed for high and low-affinity associations with post-HCT AML relapse. Among patients with a 3DL1-H donor, those transplanted from donors with the low-affinity KIR/HLA allotype combination 3DL1-H/Bw4-T80 had lower risk of relapse when compared to those with the high-affinity 3DL1-H/Bw4-I80 combination (HR 0.22; p=.003, Table) and even moreso when compared to the extra-high affinity combinations of 3DL1-H with Bw4-I80-B*2702 or B*57 (HR 0.10; p<.001). Among patients with 3DL1-L donors, those with the low-affinity KIR-HLA combination 3DL1-L/Bw4-I80 were associated with lower relapse in patients when compared to those with the high-affinity 3DL1-L/Bw4-T80 combination (HR 0.21; P=.009). Among the combined patient groups, low-affinity combinations were strongly associated with lower relapse (HR 0.24; P<.001; FigA) and lower mortality (HR 0.62; P=.03; FigB) in patients compared to the high-affinity combinations. Lack of HLA-Bw4 ligand (HLA-Bw6/Bw6) provided intermediate protection from AML relapse compared to patients in the high-affinity group (HR 0.39; P= .002; Fig 1A). Donor 3DL1-N genotypes, predictive of poor receptor expression on the NK cell surface, were not associated with HCT outcome.

Conclusions:
Protection from relapse of AML after unrelated HCT is associated with the affinity between donor KIR3DL1 and HLA-Bw4, ranging from the highly protective low-affinity donor KIR3DL1/HLA-Bw4 allotype combinations to the susceptible and “super-susceptible” effects of high- and extra-high affinity KIR/HLA combinations. These data support the consideration of KIR and HLA allotype combinations in stem cell donor selection algorithms to minimize the risk of AML relapse following HCT. Because >95% of donors are positive for KIR3DL1 and 69% of patients are positive for HLA-Bw4, incorporation of KIR3DL1/HLA-Bw4 allotypes in donor selection algorithms is a highly relevant and feasible goal.

Disclosures:
No relevant conflicts of interest to declare.