PDF(Pubmed)
Abstract：
Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor\'s Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.
摘要：
优化自然杀伤（NK）细胞同种异体反应性可以进一步改善异基因造血细胞移植（alloHCT）后的结果。供者的杀伤细胞免疫球蛋白样受体(KIR)基因型可提供这方面的重要信息。在过去的十年里,已经提出了不同的模型,旨在通过激活KIR-配体相互作用或最小化抑制性KIR-配体相互作用来最大化NK细胞活化。替代分类旨在预测供体KIR单倍型alloHCT后的结果。在本研究中,我们旨在验证提出的模型，并探索更多的分类方法。为此,我们分析了保存在协作生物库的样本,这些样本来自HLA相容的非相关干细胞捐献者,这些捐献者曾为急性髓细胞性白血病(AML)或骨髓增生异常肿瘤(MDS)患者捐献,其结局数据已报告给EBMT或CIBMTR.通过基于高分辨率扩增子的下一代测序确定供体KIR基因型。我们分析了5,017例移植的数据。alloHCT患者年龄中位数为56岁。患者在2013年至2018年之间进行了AML移植。供者-受者配对为HLA-A，-B,-C,-DRB1和-DQB1（79％）或具有单个HLA错配。56％的患者接受了清髓预处理。52％的患者接受了基于抗胸腺细胞球蛋白的移植物抗宿主病预防，32%钙调磷酸酶抑制剂为基础的预防，和7％的移植后环磷酰胺为基础的预防。我们在多变量回归分析中测试了几个先前报道的分类，但无法确认结果关联。对1,939名患者（39％）进行了探索性分析，这些患者是从具有纯合着丝粒（cen）或端粒（tel）A或B基序的供体移植的，显示供体cenB/B-telA/A复型与更好的无事件生存率（HR0.84，p=.08）和降低非复发死亡率（NRM）风险（HR0.65，p=.01）的趋势相关。当我们进一步剖析B亚型的贡献时，我们发现,只有cenB01/B01-telA/A复型与复发风险降低相关(HR0.40,p=.04),而所有亚型组合均导致NRM风险降低.这一探索性发现必须在独立的数据集中进行验证。总之,现有的证据(尚)不够一致,无法推荐在常规临床实践中使用供体KIR基因型信息进行供体选择.
