Donor KIR3DL1/Receptor HLA-Bw4-80I Combination Reduce Acute Leukemia Relapse after Umbilical Cord Blood Transplantation without in Vitro T-Cell Depletion

Objective: How to reduce relapse is still a puzzle in the treatment of acute leukemia patients with allogeneic umbilical cord blood hematopoietic cell transplantation (UCBT). Donor natural killer (NK) cell alloreactivity in UCBT can control leukemic relapse, However, NK cell function is calibrated through education, that is governed by human leukocyte antigens (HLAs), our study aim to investigate the Graft-resistant leukemia effect after transplantation of KIR3DL1 and its different ligand HLA-B subtypes(BW6, Bw4-80T, Bw4-80I).

Design and method: we retrospectivly analysed single center of 232 acute leukemia patients who underwent UCBT(myeloablative conditioning without ATG). The killer immunoglobulin-like receptor (KIR) genotype of cord blood donors was detected by SSP method, they all contains KIR3DL1. There were 104 cases of acute lymphoblastic leukemia, 112 cases of acute myeloid leukemia, 16 cases of myelodysplastic syndrome. 168 cases of transplant patients in remission period, and 64 cases of non-remission. There were 122 males and 110 females with a median age of 13 years (2-45 years). The patients were divided into three groups according to HLA-B locus, 1.patients had BW6 in both two HLA-B locus(group 1, N=86) , which means uneducated; 2.patients had HLA-Bw4-80T in the HLA-B locus(group 2, N=68), which means educated; 3.patients had HLA- Bw4-80I in the HLA-B locus(group 3, N=77), which means highly educated. The receptors were followed-up from July 31, 2012 to December 30,2017, in graft failure, neutrophil engraftment, platelet engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), relapse, overall survival (OS), and leukemia free survival (LFS).

Results: In group 3 patients, donor KIR3DL1 and receptor HLA-Bw4-80I combinations that were predictive of highly educated were associated with significantly lower relapse (hazard ratio [HR], HR = 0.49; P =0 .004) and better LFS (HR = 0.68, p = 0.014), compared with the educated(group2) and uneducated (group3) group, with no significant increase in aGVHD and cGVHD incidence. While no difference was observed in the other index in the three group.

Conclusion : Alloreactivity of NK cells demonstrated reproducible patterns of strong or weak graft-versus-leukemia (GVL) effect against leukemia blast, which is depend on donor KIR3DL1/receptor HLA-B subtype combinations. Our data suggests that donor KIR3DL1/receptor HLA-Bw4-80I combination in UCBT may achieve superior graft versus leukemia effects, lower risk for relapse among patients with acute leukemia.

Keywords: KIR, Umbilical Cord Blood Transplantation, UCBT, GVL