Ghesquières Hervé, Larrabee Beth R, Haioun Corinne, Link Brian K, Verney Aurélie, Slager Susan L, Ketterer Nicolas, Ansell Stephen M, Delarue Richard, Maurer Matthew J, Fitoussi Olivier, Habermann Thomas M, Peyrade Fréderic, Dogan Ahmet, Molina Thierry J, Novak Anne J, Tilly Hervé, Cerhan James R, Salles Gilles
Department of Hematology, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
Centre de Recherche en Cancérologie de Lyon - INSERM U 1052/CNRS UMR 5286/Centre Léon Bérard, Lyon, France.
Hematol Oncol. 2017 Dec;35(4):447-455. doi: 10.1002/hon.2305. Epub 2016 Jun 10.
Single nucleotide polymorphisms (SNPs) in FCγ-receptor genes FCGR3A (rs396991) and FCGR2A (rs1801274) influence the affinity of the Fc portion of anti-CD20 immunoglobulin G1 monoclonal antibody. Their roles in diffuse large B-cell lymphoma (DLBCL) treated with rituximab in combination with anthracycline-based chemotherapy remain controversial. To address this question, we genotyped FCGR2A and FCGR3A SNPs in two prospective DLBCL cohorts from Lymphoma Study Association trials (N = 554) and Iowa/Mayo Specialized Program Of Research Excellence (N = 580). Correlations with treatment response and hematological toxicity were assessed in Lymphoma Study Association. Correlation with event-free survival (EFS) and overall survival (OS) was performed in both cohorts, followed by a meta-analysis to increase power. Our study shows the absence of correlation between these SNPs and treatment response. Grades 3 and 4 febrile neutropenia during treatment was more frequently observed in FCGR3A VV (39%) than VF (29%) and FF (32%) carriers (p = 0.04). Our analysis for EFS and OS shows that FCGR3A was not associated with outcome. In a meta-analysis using an ordinal model, FCGR2A (per R allele) was associated with a better EFS (hazard ratio = 0.87; 95%CI, 0.76-0.99; p = 0.04) and OS (hazard ratio = 0.86; 95%CI, 0.73-1.00; p = 0.05) which was not altered after adjustment for the International Prognostic Index. Overall, our data demonstrate that patients with DLBCL with the low-affinity FCγRIIA RR had an unexpectedly better outcome than FCγRIIA H carriers. Whether rituximab efficacy is improved in FCγRIIA RR patients due a clearance reduction or other functions of FCγRIIA in DLBCL should be investigated (clinicaltrials.gov identifiers: NCT00135499, NTC00135499 NCT00140595, NCT00144807, NCT00144755, NCT01087424, and NCT00301821). Copyright © 2016 John Wiley & Sons, Ltd.
Fcγ受体基因FCGR3A（rs396991）和FCGR2A（rs1801274）中的单核苷酸多态性（SNP）会影响抗CD20免疫球蛋白G1单克隆抗体Fc部分的亲和力。它们在利妥昔单抗联合蒽环类化疗治疗弥漫性大B细胞淋巴瘤（DLBCL）中的作用仍存在争议。为解决这个问题，我们对淋巴瘤研究协会试验（N = 554）和爱荷华/梅奥卓越研究专项计划（N = 580）的两个前瞻性DLBCL队列中的FCGR2A和FCGR3A SNP进行了基因分型。在淋巴瘤研究协会中评估了与治疗反应和血液学毒性的相关性。在两个队列中均进行了与无事件生存期（EFS）和总生存期（OS）的相关性分析，随后进行荟萃分析以增强检验效能。我们的研究表明这些SNP与治疗反应之间不存在相关性。治疗期间3级和4级发热性中性粒细胞减少症在FCGR3A VV（39%）携带者中比VF（29%）和FF（32%）携带者中更频繁出现（p = 0.04）。我们对EFS和OS的分析表明FCGR3A与预后无关。在使用有序模型的荟萃分析中，FCGR2A（每个R等位基因）与更好的EFS（风险比 = 0.87；95%置信区间，0.76 - 0.99；p = 0.04）和OS（风险比 = 0.86；95%置信区间，0.73 - 1.00；p = 0.05）相关，在根据国际预后指数进行调整后该相关性未改变。总体而言，我们的数据表明，与FCγRIIA H携带者相比，具有低亲和力FCγRIIA RR的DLBCL患者预后出人意料地更好。应研究在FCγRIIA RR患者中利妥昔单抗疗效是否因清除率降低或FCγRIIA在DLBCL中的其他功能而得到改善（clinicaltrials.gov标识符：NCT00135499、NTC00135499、NCT00140595、NCT00144807、NCT00144755、NCT01087424和NCT00301821）。版权所有© 2016约翰威立父子有限公司。
