Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab.
Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab.
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DOI：
10.1158/1078-0432.ccr-15-2412
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发表时间：
2016-06-15
期刊：
影响因子：
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通讯作者：
Weide B
中科院分区：
文献类型：
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作者：
Martens A;Wistuba-Hamprecht K;Geukes Foppen M;Yuan J;Postow MA;Wong P;Romano E;Khammari A;Dreno B;Capone M;Ascierto PA;Di Giacomo AM;Maio M;Schilling B;Sucker A;Schadendorf D;Hassel JC;Eigentler TK;Martus P;Wolchok JD;Blank C;Pawelec G;Garbe C;Weide B
确定与晚期黑色素瘤患者接受伊匹单抗治疗后临床结局相关的基线外周血生物标志物。在209例患者中评估了髓源性抑制细胞（MDSC）和调节性T细胞（T细胞）的频率、血清乳酸脱氢酶（LDH）、常规血细胞计数和临床特征。终点为总生存期（OS）和最佳总体缓解。通过Kaplan-Meier和Cox回归分析进行统计学计算，包括校准和C统计学判别。低基线LDH、绝对单核细胞计数（AMC）、Lin− CD 14 +HLA-DR−/低MDSC频率，以及高绝对嗜酸性粒细胞计数（AEC）、相对淋巴细胞计数（RLC）和CD 4 + CD 25 + FoxP 3 +-Treg频率与更好的生存率显著相关，并在联合模型中考虑。43.5%具有最佳生物标志物特征的患者的缓解率为30%，中位生存期为16个月。相比之下，生物标志物最差的患者（27.5%）的缓解率仅为3%，中位生存期为4个月。不良事件的发生既不与基线生物标志物特征相关，也不与ipilimumab的临床获益相关。在另一个模型中，仅限于常规参数LDH、AMC、AEC和RLC，在主研究和独立验证队列中，有利因素的数量（4 vs. 3 vs. 2-0）也与OS相关（所有成对比较p<0.001）。低LDH、AMC和MDSC的基线特征以及高AEC、TCRP和RLC与伊匹单抗后的有利结果相关。有必要对易普利姆玛和其他治疗（例如PD-1抗体）后这些标志物的预测影响进行前瞻性研究。
To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Frequencies of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan-Meier- and Cox-regression-analysis including calibration and discrimination by C-statistics. Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. 43.5% of patients presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated with OS (p<0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. A baseline signature of low LDH, AMC and MDSCs as well as high AEC, Tregs and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g. PD-1 antibodies, is warranted.