The Direction of KIR Ligand Incompatibility Is Associated with Graft Failure and May Predict the Dominant Donor Following Double Umbilical Cord Blood Transplantation
Authors: Li Lucy , Kolk Merle , Boughan Kirsten Marie , Caimi Paolo F , Gallogly Molly M , Little Jane , Malek Ehsan , Metheny Leland , Tomlinson Ben , Cooper Brenda , de Lima Marcos , Otegbeye Folashade 
Published: October 2019

Abstract
While there is plausible evidence suggesting the benefit of natural killer (NK) cell alloreactivity in post-transplantation outcomes, there is no consensus on how such alloreactivity can be best predicted when selecting unrelated graft donors. Epitopes of HLA Class I molecules HLA-B and HLA-C are the ligands for inhibitory killer immunoglobulin-like receptors (KIRs) that regulate NK cell cytotoxicity. Based on the hypothesis that NK cell licensing in the bone marrow selects for circulating NK cells with corresponding inhibitory KIRs for self KIR ligands (KIR-L), these ligands, as determined by HLA-B/C antigens have been used as surrogates to predict NK cell alloreactivity in mismatched transplants. There is also the potential for alloreactivity by NK cells in the host versus graft (HvG) direction particularly in cord blood transplantation where reduced intensity conditioning is common. We examined cord blood transplantations at our institution to determine the impact of donor/recipient KIR ligand mismatch, and its direction, on graft failure.
Methods: We analyzed the Stem Cell Transplant database of all cord blood transplants (CBT) performed at University Hospitals Seidman Cancer Center between December 2010 and April 2018. Data extracted from electronic medical record review included demographics, indication for transplant, disease status at time of transplant, conditioning regimen, graft versus host disease (GVHD) prophylaxis including the use of antithymocyte globulin (ATG) and post transplantation outcomes. For the cohort we computed KIR ligands for transplant recipients and cord blood unit(s), then predicted direction of alloreactivity using the KIR ligand calculator available online (https://www.ebi.ac.uk/ipd/kir/ligand.html). We determined the relative risk of developing graft failure as well as summary statistics of time to neutrophil engraftment and achieving a stable lymphocyte count of 500/ul or more in those that engrafted.
Results: We identified 67 patients that received cord blood transplants for which donor and recipient KIR-L could be adequately computed. Three of these patients required a second cord blood transplant for graft failure, resulting in a total of 70 CBTs. Demographics, disease characteristics and treatment regimens are outlined in Table 1. There were KIR-L mismatches (MM) in the HvG and GvH direction in 32 and 31 recipient-cord blood unit pairs respectively. While there were no KIR-L MM in 26 transplants, 7 transplants had KIR-L mismatches in both GvH and HvG directions. There was an increased risk of graft failure in recipients of HvG-directed KIR-L MM transplants (R.R 2.15; p=0.063) with this trend most significant when the mismatch was in HLA-C ligand (R.R 2.46; p=0.027); Table 2. Out of 8 double CBTs where 1 cord unit had HvG-directed KIR-L MM, the non-mismatched unit fully engrafted in 7 (75%) cases. In 1 case the non-mismatched unit shared donor chimerism with the KIR-L MM unit at 85% and 15% respectively till 10 months post-transplant. In 6 double CBTs where there was KIR-L MM from only 1 cord unit in the GvH-direction, 4 (67%) of such units became the dominant graft. Of 8 double CBTs in which both cord units had KIR-L MM in the HvG direction there was graft failure in 3 (37.5%). The time to neutrophil engraftment and lymphocyte recovery in the patients that engrafted was not significantly impacted by KIR-L incompatibility (Table 3).
Conclusions: From this study we see an increased likelihood of graft failure when KIR-ligand incompatibility exists in the host versus graft direction for CBT. There is also a trend in favor of engrafting the cord unit that is KIR-L mismatched in the graft versus host direction against the second cord in double CBT. These factors should be considered when selecting cord units for double CBT as well as in making single cord decisions where multiple options are available.

Disclosures
Little: Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding; PCORI: Research Funding; NHLBI: Research Funding. Malek:Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.