Incompatible Inhibitory KIR Ligands Contribute To Lower Survival Rates in Leukemia Patients Receiving T-Replete Hematopoietic Cell Transplants (HCTs).

Natural killer (NK) cells are becoming increasingly recognized as an important part of the immune system. Killer Ig-like receptors (KIRs) are the major form of receptors used by human NK cells. KIRs transmit either inhibitory or activating signals regulating NK cell activity. Some inhibitory KIRs specifically recognize HLA-A, B or -Cw allotypes on target cells. Thus differences in inhibitory ligand (iKIRL) phenotypes between donors and patients could result in NK cell alloreactivity that further results in different HCT outcomes. To test this hypothesis, the present study evaluated 362 patients with either ALL (99), AML/MDS (141), or CML (122). The patients were transplanted (1996~2003) with T-replete bone marrow, or peripheral blood stem cells from unrelated donors. High resolution HLA typing with DNA-based methods had been prospectively performed for donor selection. The KIR genes of patients and donors were retrospectively typed by a multiplex PCR-SSP method. The cohort was divided into three groups by the HLA and KIR profiles: 247 cases with matched HLA at the antigen level of HLA-A, B, Cw, DRB1, and DQB1 (MH), 64 with mismatched HLA (mMH) and 51 with mMH plus mismatched iKIRL (mMH+miKIRL). A significantly different rate (P=0.009) of estimated one year overall survival was found between the MH (61%, 95%CI 55–67%), the mMH (46%, 34–59%), and the mMH+miKIRL (29%, 18–43%) groups. When analyzing the event free survival, a similar difference (P=0.003) was observed between the MH (57%, 51–63%), the mMH (43%, 32–56%) and the mMH+miKIRL (25%, 15–39%) groups. Further analysis demonstrated a different rate (P=0.02) of relapse between the MH (two-year estimation: 21%, 16–28%), the mMH (16%, 7–31%), and the mMH+miKIRL (36% 18–58%) groups. That the MH group experienced more relapses than the mMH is consistent with the GvL effect. The mMH+miKIRL group experienced the most relapses implied miKIRL undermine the GvL effect. We also tested the influence of lacking iKIRL in patients within the MH group, and found a significant survival difference (P=0.05) among the patients lacking two iKIRLs (n=67, 54% 42%–65%), one iKIRL (n=104, 59% 49%–68%), or none (n=76, 70% 58%–79%). This finding contrasts with the previously reported beneficial role of potential NK cell alloreactivity in T-depleted HCT. Additional studies are required to resolve these issues.