Impact of Killer Immunoglobulin Receptor (KIR) Ligand Incompatibility in Nonmyeloablative Bone Marrow Transplantation (BMT) from Haploidentical Donors.
Authors: Symons Heather J. , Leffell M. Sue , Rossiter Nancy D. , Sugar Elizabeth , Luznik Leo , Phelps Michele , Crawford Angelita , Levy M. Yair , Jones Richard J. , Fuchs Ephraim J. 
Published: April 2020

Abstract
Donor vs. recipient natural killer (NK) cell alloreactivity in mismatched (haploidentical) bone marrow transplantation (BMT) has been defined as a mismatch between killer inhibitory receptors (KIR) on donor NK cells and their inhibitory HLA class I ligands on recipient cells. Data reporting the impact of KIR incompatibility in the haploidentical BMT setting have been controversial. Here, we examine the effect of KIR ligand mismatches in 60 patients with advanced hematologic malignancies who were enrolled in a clinical trial of nonmyeloablative haploidentical BMT (“mini-haploBMT”). All patients were conditioned prior to transplantation with fludarabine, low dose cyclophosphamide (Cy), and 200 cGy TBI, and after transplantation received high dose Cy, mycophenolate mofetil (MMF) and tacrolimus. The median age of transplant recipients was 48 years (range, 1–71years). Patients received a median of 1.27x 108/kg mononuclear cells/kg and a median of 3.9 x 106 CD34+ cells/kg. Donor-recipient pairs had an average of 3 out of 8 HLA antigen mismatches in both the host-vs.-graft (HVG) and graft-vs.-host (GVH) directions. Graft failure occurred in 12/58 (21%) evaluable patients, and grade 3–4 GVHD occurred in 7/60 patients (11.7%). Median time to disease progression was 222 days and median overall survival was 255 days. The median follow-up at the time of this analysis was 251 days (range 41–1715 days). KIR mismatches were identified via KIR genotyping (KIR genes determined by SSP from genomic DNA extracts) as well as via the previously described receptor:ligand model which identifies the presence of inhibitory KIR on donor cells, with absence of HLA ligand on host cells. Utilizing the receptor:ligand model, our results demonstrate an improvement in time to relapse (TTR) in patients with ≥1 inhibitory KIR mismatches (32 patients, median TTR 359 days) versus no mismatches (27 patients, median TTR 185 days) (p=0.036) and an improved overall survival (OS) in patients with ≥1 inhibitory KIR mismatches (32 patients, median OS 622 days) versus no mismatches (27 patients, median OS 208 days) (p=0.008). No significant difference in OS or TTR was found when patients were separated by disease type (myeloid versus lymphoid; OS p= 0.095 vs. p=0.1 and TTR p=0.2 vs. 0.1). There were also no significant differences in TTR or OS when using the KIR genotyping method of identifying mismatches. No differences in Grades 2–4 graft-versus-host disease (GVHD) or engraftment were found based on the presence of inhibitory or stimulatory KIR mismatches, although the small numbers of patients with GVHD or engraftment failure prevent a definitive analysis. KIR ligand incompatibility in the GVH direction is associated with a prolonged time to relapse and improved overall survival after nonmyeloablative haploidentical BMT. These findings may warrant the selection of donors based upon KIR ligand incompatibility.