Patients Lacking a KIR-Ligand of HLA Group C1 or C2 Have a Lower Incidence of Grades II-IV Acute Graft-Vs-Host Disease after Umbilical Cord Blood Transplantation

Introduction: Natural killer (NK) cells are important part of the innate immunity defense system and play an antiviral, anti-tumor and immunomodulatory role in the body's immune response. NK cells are the first lymphocytes recovered after umbilical cord blood transplantation (UCBT). By attacking on the host cell, leukemia cells and antigen-presenting cells, the allogeneic reactive NK cells help realize successful implantation, mediate Graft-versus-leukemia (GVL) to reduce the recurrence, and lower the incidence of graft versus host disease (GVHD) respectively, thereby improving overall survival (OS) ultimately. The effect is based on the interaction of killer-cell immunoglobulin-like receptors (KIR) of donor NK cells with ligands of the major histocompatibility complex found on the surface of the target cells. HLA-C1 subtypes provide the ligand for KIR2DL2 and KIR2DL3, and the HLA-C2 subtypes for KIR2DL1. Therefore, we want to study the impact of the killer cell immunoglobulin like receptor/human leukocyte antigen(KIR/HLA) receptor ligand model in UCBT

Method: Between July 2012 and June 2018, 270 patients with malignant hematologic disease receiving single-unit UCBT were divided into two groups based on the absence or the presence of one of the C-ligands for inhibitory KIR. Group 1 (n=174) patients lacked a C-ligand for inhibitory KIR present on UCB NK cells, (patients homozygous C1/C1 or C2/C2). Group 2 (n=96) patients had heterozygous C1/C2 in which KIR-mediated GVL effect was not expected (presence of both C ligands for inhibitory KIR in the receptor). Group 1 (mean age 13y, r 1-62; male 90) and group 2 (mean age 14.5y, r 1-59; male 56) had no significant differences in age, gender, weight, underline diseases, state of disease, and HLA match (low-resolution). All patients' conditioning regimen was myeloablative and did not contain anti-thymocyte globulin (ATG). Cyclosporine combined with mycophenolate mofetil was applied as GVHD prophylaxis.

Results: The median follow-up time since the transplant for the surviving patients was 25 months (11-84 months). We compared some indicators related to UCBT between the two groups. The median time to neutrophil engraftment for group 1 and 2 was 16 days vs. 17 days (P = 0.705), and median time to platelet engraftment was 35 days vs.38.5 days (P = 0.317). The cumulative incidence of II-IV acute GVHD in 100 days was 42.5% (38.7% for group 1 vs. 50.0% for group 2, P = 0.0751), but multi-variate analysis showed that HLA-C ligand absence was an independent risk factor for II-IV acute GVHD after transplantation (HR=1.5280, P=0.0356). Patients with absence of a C-ligand for inhibitory KIRs (Group 1) showed a lower relapse rate than patients with both C-ligands (group 2):17.7% VS 22.7% at 3 years (P=0.288). The 3-year OS was 69.3% for group 1 and 60.5% for group 2 (P=0.0792). Non-relapse mortality for group 1 was 16.8% and for group 2 was 20.8% (P=0.328). There was no statistically significant difference between the two groups in 3-year disease-free survival (64.9% vs 55.4%, P=0.0819).

Conclusion: Our results suggest that patients lacking a KIR-ligand of HLA group C1 or C2 had a lower incidence of grades II-IV acute GVHD after UCBT. The absence of HLA-C ligands in recipients had no statistically significant effect on other transplant survival prognosis, which may be related to the conditioning regimen without removing T cells. A beneficial impact mediated by NK alloreactivity between UCB and recipient may be observed during longer follow-up. Therefore, the absence of a C-ligand could be considered as one of the critical factors for the selection of UCBT.

No conflict of interest to declare.