KIR Ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy
ABSTRACT Recurrent malignancy remains a significant complication after allogeneic hematopoietic cell transplantation (HCT). Efforts to decrease relapse have included donor lymphocyte infusion to stimulate donor anti-recipient T-cell allorecognition of major and minor histocompatibility differences. Recently, alloreactive effects of donor natural killer cell-mediated inhibitory killer immunoglobulin-like receptor (KIR) recognition of recipient HLA-C and -B ligands have been described. We examined KIR ligand effects on risk of relapse in 1770 patients undergoing myeloablative T-replete HCT from HLA-matched or -mismatched unrelated donors for the treatment of myeloid and lymphoid leukemias. KIR ligands defined by HLA-B and -C genotypes were used to determine donor-recipient ligand incompatibility or recipient lack of KIR ligand. Among HLA-mismatched transplantations, recipient homozygosity for HLA-B or -C KIR epitopes predicted lack of KIR ligand and was associated with a decreased hazard of relapse (hazard ratio, 0.61; 95% confidence interval, .043-0.85; P = .004). Absence of HLA-C group 2 or HLA-Bw4 KIR ligands was associated with lower hazards of relapse (hazard ratio, 0.47; 95% confidence interval, 0.28-0.79, P = .004; hazard ratio, 0.56; 95% confidence interval, 0.33-0.97; P = .04, respectively). The decrease in hazard of relapse in patients with acute myelogenous leukemia was similar to that in patients with chronic myelogenous leukemia and acute lymphoblastic leukemia (P = .95). Recipient homozygosity for HLA-B or -C epitopes that define KIR ligands is likely to be a predictive factor for leukemia relapse after myeloablative HCT from HLA-mismatched unrelated donors. This effect was not observed in HLA-identical unrelated transplants.
SourceAvailable from: Markus Uhrberg[Show abstract] [Hide abstract]
ABSTRACT: A role for HLA class I polymorphism in childhood acute lymphoblastic leukemia (ALL) has been suggested for many years but unambiguous associations have not been found. Here, we show that the HLA-C-encoded supertypic epitope C2, which constitutes a high affinity ligand for the inhibitory natural killer (NK) cell receptor KIR2DL1, is significantly increased in ALL patients (n = 320; p = 0.005). Stratification for ethnicity and disease subtype revealed a strong association of C2 with B-ALL in German cases (p = 0.0004). The effect was independent of KIR2DS1 and KIR2DL1 allelic polymorphism and copy number. Analysis of clinical outcome revealed a higher incidence of late relapse (>2.5 years) with increasing number of C2 alleles (p = 0.014). Our data establish C2 as novel risk factor and homozygosity for C1 as protective for childhood B-ALL supporting a model in which NK cells are involved in immunosurveillance of pediatric B-ALL via interaction of KIR with HLA-C ligands.Blood 08/2014; 124(14). DOI:10.1182/blood-2014-05-572065 · 9.78 Impact Factor
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ABSTRACT: Relapse of acute lymphoblastic leukemia remains a major cause of death in patients following allogeneic hematopoietic stem cell transplantation. Several factors may affect the concurrence and outcome of relapse, which include graft-versus-host disease, minimal residual disease or intrinsic factors of the disease, and transplantation characteristics. The mainstay of relapse prevention and treatment is donor leukocyte infusions, targeted therapies, second transplantation, and other novel therapies. In this review, we mainly focus on addressing the impact of graft-versus-host disease on relapse and the prophylaxis and treatment of acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation. We also make recommendations for critical strategies to prevent relapse after transplantation and challenges that must be addressed to ensure success.OncoTargets and Therapy 01/2015; 8:405-12. DOI:10.2147/OTT.S78567 · 1.34 Impact Factor
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ABSTRACT: The impact of HLA and KIR ligand mismatching on the outcome of hematopoietic stem cell transplantation (HSCT) remains unclear. Previous reports have identified considerable ethnic differences in the impact of HLA and KIR ligand mismatches, as well as KIR ligand status, on HSCT; however, to date, no data has been acquired in Korean adult patients. We investigated the association of high-resolution HLA matching on five loci (HLA-A, -B, -C, -DRB1, and -DQB1), KIR ligand mismatching, and KIR ligand status on the outcome of allogeneic HSCT from unrelated donors in 154 Korean adult patients treated at Seoul National University Hospital. In a multivariate analysis, less than 9/10 allelic matches in five HLA loci was an independent risk factor for acute graft-versus-host disease (GVHD) (grade II to IV) (P=0.019, odds ratio [OR]=2.7). In addition, HLA-A allele mismatching was increasingly prevalent in patients with acute GVHD compared to patients without (61.9% vs. 34.5%, P=0.06). For KIR ligand status, the patient and donor combination of both C1/C1 ligands showed better event-free and overall survival than combinations with C2 ligand patients or donors (P=0.048, P=0.034, respectively) by log-rank test. Korean adult transplant patients with less than 9 of 10 HLA allele matches in the HLA-A, -B, -C, -DRB1, and DQB1 loci have a higher likelihood of developing acute GVHD (grade II to IV). Impact of KIR ligand status on clinical outcome should be further studied in a larger patient population.Annals of Laboratory Medicine 01/2015; 35(1):111-7. DOI:10.3343/alm.2015.35.1.111 · 1.48 Impact Factor