Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab
Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab
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DOI：
10.1186/s40425-019-0538-8
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发表时间：
2019-03-12
影响因子：
10.9
通讯作者：
Sondel, Paul M.
中科院分区：
文献类型：
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作者：
Erbe, Amy K.;Wang, Wei;Sondel, Paul M.
背景资料：ECOG-ACRIN癌症研究小组评估了新诊断的低肿瘤负荷滤泡性淋巴瘤（FL）患者的利妥昔单抗治疗方案。所有患者均接受4周一次的利妥昔单抗诱导治疗。临床应答的患者随机接受利妥昔单抗治疗，每13周一次（“维持”），与不接受额外的利妥昔单抗治疗直至进展（“非维持”）。基于“至利妥昔单抗治疗失败的时间（TTRF）"，研究委员会报告说，在这种情况下，维持利妥昔单抗治疗没有总体获益。肿瘤反应性mAb，如利妥昔单抗，触发自然杀伤（NK）细胞。NK细胞应答部分地通过NK细胞上的杀伤免疫球蛋白样受体（KIR）之间的相互作用及其与KIR配体的相互作用来调节。在另一项对神经母细胞瘤患儿使用不同mAb治疗的研究中，我们发现某些KIR/KIR配体基因型与预后改善相关。在这里，我们评估了FL患者的一个子集是否显示出改善的结果，从维护利妥昔单抗基于这些相同的KIR/KIR-配体genotype.Methods：基因型KIR/KIR-配体进行了测定和评估与结果的关联[反应持续时间，TTRF和%肿瘤缩小]作为事后分析的III期试验。我们的主要目的是评估特定的KIR/KIR-配体基因型关联，随后在随访分析中单独预先指定的KIR/KIR-配体基因型关联。基因型与临床结果相关性的统计分析包括：对数秩检验和考克斯比例风险回归模型，以评估反应持续时间和TTRF;方差分析（ANOVA）用于评估肿瘤缩小%。我们发现患者沿着KIR 2DL 2及其配体（HLA-C1）和KIR 3DL 1及其配体（HLA-Bw 4）遗传，比没有这种基因型的患者有更好的结果。此外，携带KIR 2 DL 2和HLA-C1沿着KIR 3 DL 1和HLA-Bw 4的患者如果接受维持治疗，也显示出缓解持续时间和肿瘤缩小的改善，而不携带该基因型的患者在接受维持治疗时没有显示出这种改善。这里提供的数据表明，通过某些KIR/KIR配体鉴定的FL患者的子集，结果得到改善，并可能受益于额外的利妥昔单抗治疗。总之，这表明肿瘤反应性mAb治疗对某些患者的疗效受到NK细胞上KIR的影响。然而，在以临床可行的方式考虑这些基因型之前，这些发现需要在其他研究中进行独立验证。
Background: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximabfailure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes.Methods: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage.Results: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance.Conclusions: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.