Bone Marrow Minimal Residual Disease Was an Early Response Marker and a Consistent Independent Predictor of Survival After Anti-GD2 Immunotherapy
Bone Marrow Minimal Residual Disease Was an Early Response Marker and a Consistent Independent Predictor of Survival After Anti-GD2 Immunotherapy
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DOI：
10.1200/jco.2014.57.6777
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发表时间：
2015-03-01
影响因子：
45.3
通讯作者：
Cheung, Irene Y.
中科院分区：
文献类型：
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作者：
Cheung, Nai-Kong V.;Ostrovnaya, Irina;Cheung, Irene Y.
目的免疫治疗是高危神经母细胞瘤儿童的标准治疗，其中骨髓 (BM) 是主要转移部位。 BM 中微小残留病 (MRD) 的早期反应标志物也可预测生存，有助于个体化患者治疗。 患者和方法在实现首次缓解 (n = 163)、原发性难治性疾病 (n = 102) 或第二次缓解 (n = 95) 后，4 期神经母细胞瘤儿童接受抗 GD2 3F8 抗体免疫治疗。使用四标记物组（B4GALNT1、PHOX2B、CCND1 和 ISL1）通过定量逆转录聚合酶链式反应测量 3F8 治疗前和第 2 周期后 (postMRD) 的 BM MRD。使用 Kaplan-Meier 方法估计无进展生存期 (PFS) 和总生存期 (OS)。在单变量和多变量分析中对预后变量进行了测试，并使用 Cox 回归模型对 MRD 标记进行单独评估和组合评估，作为二元复合（postMRD：0 和 1）和等和（postMRDSum：0 至 4），其预测准确性由一致性指数确定。 结果当在第 2 周期后评估 BM 时，单个标记对 PFS 和 OS 具有高度预测性。当它们在 postMRDSum 中组合时，预测精度得到提高。多变量模型考虑了单变量分析中所有重要的变量，确定 postMRDSum 可独立预测 PFS 和 OS。当 OS 模型还包括缺失的杀伤性免疫球蛋白样受体配体、人抗小鼠抗体反应和入组疾病状态时，一致性指数为 0.704。 结论 两个周期免疫治疗后的 BM MRD 被证实是早期反应标志物和一致的独立生存预测因子。 (C) 2015 年美国临床肿瘤学会
PurposeImmunotherapy is a standard of care for children with high-risk neuroblastoma, where bone marrow (BM) is the predominant metastatic site. Early response markers of minimal residual disease (MRD) in the BM that are also predictive of survival could help individualize patient therapies.Patients and MethodsAfter achieving first remission (n = 163), primary refractory disease (n = 102), or second remission (n = 95), children with stage 4 neuroblastoma received anti-GD2 3F8 antibody immunotherapy. BM MRD before 3F8 treatment and after cycle 2 (postMRD) was measured using a four-marker panel (B4GALNT1, PHOX2B, CCND1, and ISL1) by quantitative reverse transcription polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic variables were tested in both univariable and multivariable analyses, and MRD markers were further assessed individually and in combination as binary composite (postMRD: 0 and 1) and as equal sum (postMRDSum: 0 to 4) using the Cox regression models, and their predictive accuracy was determined by the concordance index.ResultsWhen BM was evaluated after cycle 2, individual markers were highly predictive of PFS and OS. The prediction accuracy improved when they were combined in postMRDSum. A multivariable model taking into account all the variables significant in the univariable analyses identified postMRDSum to be independently predictive of PFS and OS. When the model for OS also included missing killer immunoglobulin-like receptor ligand, human antimouse antibody response, and the enrollment disease status, the concordance index was 0.704.ConclusionBM MRD after two cycles of immunotherapy was confirmed as an early response marker and a consistent independent predictor of survival. (C) 2015 by American Society of Clinical Oncology