KIR-Ligand Incompatibility in the Graft-Versus-Host Direction Is Associated with Better Outcomes after Unrelated Cord Blood Stem Cell Transplantation for Acute Leukemia in Complete Remission
Authors: Willemze Roelof , Rodrigues Celso arrais , Labopin Myriam , Sanz Guillermo , Michel Gerard , Socié Gerard , Rio Bernard , Sirvent Anne , Renaud Marc , Madero Luis , Mohty Mohamad , Ferra Christelle , Garnier Federico , Garcia Juan , Lecchi Lucilla , Koegler Gesine , Beguin Yves , Navarrete Cristina , Devos Timothy , Ionescu Irina , Boudjedir Karim , Herr Andrée-Laure , Gluckman Eliane , Rocha Vanderson 
Published: April 2020

Abstract
HLA class I, killer-cell immunoglobulin-like receptor (KIR) ligands which are missing in the recipient may trigger cytotoxicity of donor NK cells leading to graft-versus- host disease (GvHD) and/or graft-versus-leukemia reactions. Donor KIR(-ligand) incompatibility in the graft-versus-host (GvH) direction is associated with decreased relapse incidence (RI) and improved disease-free survival (DFS) in haplo-identical and HLA-mismatched unrelated hematopoietic stem cell transplantation (HSCT). Since it is unknown whether KIR-ligand mismatching impacts outcomes in unrelated cord blood stem cell transplantation (UCBT), we studied patients reported to Eurocord Registry with acute leukemia in complete remission (CR) with available high resolution typing of HLA-A, -B and -C in recipient/donor pairs who received a single UCBT. Patients and donors were categorized to their KIR-ligand groups by determining whether or not they expressed: HLA-C group 1 or 2, HLA-Bw4 and HLA-A3 or -A11. A total of 218 patient-donor pairs met the eligibility criteria. The patients had ALL (n=124) or AML (n=94) and were transplanted in 1st CR (n=105), 2nd CR (n=91) or &gt;2nd CR (n=22). Median age was 13.4 yrs, weight 49 kg, and nucleated cell dose infused was 3.0×10E7/kg. The cord blood was HLA identical (6/6) in 21, 5/6 in 91, 4/6 in 91 and &lt;4/6 in 15. Conditioning was myeloablative (84%) or reduced intensity (16%), and included ATG in 80%. Forty-one donors were HLA-C, 12 HLA-Bw4 and 22 HLA-A3/-A11 KIR-ligand mismatched in the GvH direction with the patient whereas fifty-one patients were HLA–C group 1 or 2, 19 HLABw4 and 18 HLA-A3/-A11 KIR-ligand mismatched in the HvG direction with the donor. When studying only donor-patient pairs in the GvH direction a total of sixty-nine patients had a KIR-ligand mismatched (KIR+) donor and 149 had not (KIR−). There were no statistical differences for patient-, disease- and transplantion-related factors between the KIR+ and KIR− group, except for more cytogenetically bad risk AML patients in the KIR+ group. HLA-C group 1 and 2, and HLA-A3/-A11, KIR-ligand incompatible UCBT showed independently a trend to improved DFS (p=0.09 and p=0.13, respectively). Analysis of the combined HLA-A, -B and -C KIR-ligand (mis)matches showed no statistical association with neutrophil recovery (81±4% KIR+, 79±3% KIR− group, p=0.21), non-relapse mortality (25±6% KIR+, 32±4% KIR−, p=0.34), acute GvHD (27±5% KIR+, 29±3% KIR−, p=0.82) and chronic GvHD (18±4% KIR+, 14±3% KIR−, p=0.38). However, differences were shown in RI (20±6% KIR+, 37±4% KIR−, p=0.03), DFS (55±7% KIR+, 31±4% KIR−, p=0.005) and overall survival (57±7% KIR+, 40±4% KIR−, p=0.02). In multivariate analysis, donor KIR-ligand incompatibility was associated with decreased RI (HR=0.53, p=0.05), increased DFS (HR=2.05, p=0.016) and overall survival (HR=2, p=0.004). In subgroup analysis for AML: RI for KIR+ vs KIR− was 5±4% vs 36±7% (p=0.005) and DFS 73±10% vs 38±7% (p=0.012); and for ALL: RI was 29±8% vs 37±6% (p=0.71) and DFS 44±9% vs 27±6% (p=0.10), respectively. The use of KIR-ligand incompatible donors in UCBT resulted in a lower RI and increased DFS and overall survival, especially in AML. If these results are confirmed in a larger series of patients KIR-ligand incompatibility in the GvH direction might be considered as a criterion of cord blood donor choice.