General AML

An association between KIR3DL1 and HLA-B subtypes and AML HCT outcomes

Combinations of Killer Cell Immunoglobulin-Like Receptor 3DL1 (KIR3DL1, recognizes HLA [Human Leucocyte Antigen] allotypes that bear the Bw4 motif) and HLA subtypes can predict relapse and mortality in Acute Myeloid Leukemia (AML) patients who underwent HLA-matched allogenic Hematopoietic Cell Transplantation (HCT) according to a study published ahead of print in the Journal of Clinical Oncology on 18th May 2017.

Lack of HLA ligand for donor Killer Immunoglobulin-Like Receptor (KIR) is associated with superior Natural Killer (NK) cell reactivity and lower relapse in patients who underwent HCT. The rationale for this study by Jeanette E. Boudreau and colleagues from the Memorial Sloan Kettering Cancer Center was to determine whether varied strengths of inhibition of NK cells among KIR3DL1 polymorphic subtypes were associated with outcomes of AML patients post-HCT.

Using an algorithm and in vitro analysis, the authors identified three donor subgroups that differed by their inhibitory and cytotoxic NK potential; donors with KIR3DL1-L + Bw4-80T or KIR3DL1-L + Bw4-80I (Strong Inhibiting Pair), KIR3DL1 + Bw6-/Bw6, KIR3DL1-N + Bw4-80I, or KIR3DL1-N + Bw4-80T (Non-Inhibiting Pair), and KIR3DL1-H + Bw4-80T or KIR3DL1-L + Bw4-80I (Weak Inhibiting Pair). The impact of these subtype combinations on post-HCT outcomes were retrospectively studied in 1,328 AML patients who received an allograft from a 9/10 or 10/10 HLA-matched unrelated donor.

The key results of the study were:
  • Weak Inhibiting Pairs and Non-Inhibiting Pairs (n = 994) were significantly associated with lower relapse (HR = 0.72, P = 0.004) and mortality (HR = 0.84, P = 0.030) compared to Strong Inhibiting Pairs (n = 334)
  • The protective effects of Weak or Non-Inhibiting Pairs on relapse (HR = 0.54, P < 0.001) and mortality (HR = 0.74, P < 0.009) were more evident in high-risk patients with all KIR ligands
  • Combinations of Weak and Non-Inhibiting KIR3DL1 and HLA-B subtype with KIR2DS1/HLA-C1 conveyed the lowest relapse and highest survival to patients

Overall, the authors concluded by stating that “refining donor selection algorithms to include KIR3DL1/HLA-B subtype analysis to avoid strong inhibition donors may reduce relapse and improve survival” among patients with AML.

A prospective clinical trial (NCT02450708) evaluating whether screening for KIR3DL1 subtypes among HLA-matched HCT donors would have any effect on the outcomes of AML patients is currently underway. The primary and secondary outcome of the study is relapse and overall survival, respectively.

 Abstract

Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells-upregulated in the post-HCT environment-signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.

References
  1. Boudreau J. E. et al. KIR3DL1/ HL A-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation. J Clin Oncol. 2017 May 18. DOI: 10.1200/JCO.2016.70.7059. [Epub ahead of print].