Corresponding Authors: Michael Andreeff, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77054.
Mol Cancer Ther. 2013 Dec;12(12):2940-9. doi: 10.1158/1535-7163.MCT-13-0692. Epub 2013 Oct 3.
As acute myelogenous leukemia (AML) patient response to cytarabine-based standard-of-care treatment is variable, stratification into subgroups by biomarker-predicted response may lead to improved clinical outcomes. Here, we assess cell mitochondrial depolarization to proapoptotic signaling BH3-only peptides as a surrogate for the function of Bcl-2 family proteins to address clinical response to cytarabine-based therapy in patients with AML (N = 62). Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate specimens were obtained from newly diagnosed patients with AML, viably preserved, and assayed by flow cytometry following BH3 profile assay with individual BH3 peptides. Mann-Whitney analysis indicates biomarker correlation with response to induction therapy: Notably, BIM priming was highly significant (P = 2 × 10(-6)) with a compelling sensitivity/specificity profile [area under curve (AUC) = 0.83; 95% confidence interval (CI), 0.73-0.94; P = 2 × 10(-10)]. Multivariate analysis indicates improved profiles for BIM readout + patient age (AUC = 0.89; 95% CI, 0.81-0.97) and BIM + patient age + cytogenetic status (AUC = 0.91; 95% CI, 0.83-0.98). When patients were stratified by cytogenetic status, BIM readout was significant for both intermediate (P = 0.0017; AUC = 0.88; 95% CI, 0.71-1.04) and unfavorable (P = 0.023; AUC = 0.79; 95% CI, 0.58-1.00) risk groups, demonstrating predictive power independent of cytogenetics. Additional analyses of secondary clinical endpoints displayed correlation between overall survival (P = 0.037) and event-free survival (P = 0.044) when patients were stratified into tertiles by BIM peptide response. Taken together, these results highlight the potential utility of BH3 profiling in personalized diagnostics of AML by offering actionable information for patient management decisions.
由于急性髓系白血病 (AML) 患者对基于阿糖胞苷的标准治疗的反应各不相同，因此通过生物标志物预测的反应对其进行分组可能会改善临床结局。在这里，我们评估了细胞线粒体去极化对促凋亡信号 BH3 仅肽的反应，作为 Bcl-2 家族蛋白功能的替代指标，以解决 AML 患者基于阿糖胞苷治疗的临床反应问题（N = 62）。从新诊断的 AML 患者中获得外周血单核细胞 (PBMC) 或骨髓抽吸标本，进行活保存，并通过 BH3 谱分析用单个 BH3 肽进行流式细胞术分析。Mann-Whitney 分析表明，生物标志物与诱导治疗反应相关：值得注意的是，BIM 引发具有高度显著性（P = 2×10(-6)），具有令人信服的敏感性/特异性特征[曲线下面积 (AUC) = 0.83；95%置信区间 (CI)，0.73-0.94；P = 2×10(-10)]。多变量分析表明，BIM 读数+患者年龄的改善特征（AUC = 0.89；95%CI，0.81-0.97）和 BIM+患者年龄+细胞遗传学状态（AUC = 0.91；95%CI，0.83-0.98）。当根据细胞遗传学状态对患者进行分层时，BIM 读数对中危（P = 0.0017；AUC = 0.88；95%CI，0.71-1.04）和高危（P = 0.023；AUC = 0.79；95%CI，0.58-1.00）风险组均具有显著性，证明了独立于细胞遗传学的预测能力。对次要临床终点的进一步分析显示，当患者按 BIM 肽反应分为三分位时，总生存（P = 0.037）和无事件生存（P = 0.044）之间存在相关性。综上所述，这些结果突出了 BH3 谱分析在 AML 个体化诊断中的潜在效用，为患者管理决策提供了可操作的信息。
