BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia.
BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia.
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DOI：
10.1158/1535-7163.mct-13-0692
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发表时间：
2013-12
影响因子：
5.7
通讯作者：
Andreeff M
中科院分区：
文献类型：
--
作者：
Pierceall WE;Kornblau SM;Carlson NE;Huang X;Blake N;Lena R;Elashoff M;Konopleva M;Cardone MH;Andreeff M
由于急性髓系白血病(AML)患者对以阿糖胞苷为基础的标准治疗的反应是不同的，根据生物标记物预测的反应分成不同的亚组可能会导致改善临床结果。在这里，我们评估细胞线粒体去极化，以促进凋亡的信号，仅BH3-多肽作为Bcl2家族蛋白功能的替代品，以解决急性髓细胞白血病患者(n=62)对基于阿糖胞苷治疗的临床反应。采集初诊AML患者外周血单个核细胞(PBMC)或骨髓抽吸物(BM)标本，活体保存后用BH3多肽进行BH3谱分析后用流式细胞仪进行检测。Mann-Whitney分析表明生物标记物与诱导治疗的反应相关：值得注意的是，BIM启动非常显著(p=2×10−6)，具有令人信服的敏感性/特异性(Auc=0.83；CI[0.73，0.94]；p=2×10−10)。多变量分析显示，BIM读数+患者年龄(AUC=0.89；CI[0.81，0.97])和BIM+患者年龄+细胞遗传学状态(AUC=0.91；CI[0.83，0.98])的特征有所改善。当患者按细胞遗传学状态分层时，BIM读数对中等风险组(p=0.0017；AUC=0.88；CI[0.71，1.04])和不良风险组(p=0.023；AUC=0.79；CI[0.58，1.00])均有显著意义，显示出独立于细胞遗传学的预测力。对次级临床终点的其他分析表明，当患者按BIM多肽反应分层时，总存活率(OS；p=0.037)和无事件存活率(EFS；p=0.044)之间存在相关性。综上所述，这些结果突出了BH3分析在AML个性化诊断中的潜在效用，它为患者管理决策提供了可操作的信息。
As Acute Myeloid 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 pro-apoptotic signaling BH3-only peptides as a surrogate for the function of Bcl-2 family proteins to address clinical response to cytarabine-based therapy in AML patients (n=62). Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate (BM) specimens were obtained from newly diagnosed AML patients, 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 (AUC=0.83; CI[0.73,0.94]; p=2×10−10). Multivariate analysis indicates improved profiles for BIM readout + patient age (AUC=0.89; CI[0.81,0.97])and BIM + patient age +cytogenetic status (AUC=0.91; 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; CI[0.71,1.04]) and for unfavorable (p=0.023; AUC=0.79; CI[0.58,1.00]) risk groups, demonstrating predictive power independent of cytogenetics. Additional analyses of secondary clinical endpoints displayed correlation between overall survival (OS; p=0.037) and event-free survival (EFS; 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.