Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen

项目总结 老年患者和复发/难治性急性髓系白血病(AML)或 骨髓增生异常综合征(MDS)仍然很差。文奈德是一种选择性的bcl2抑制剂，最近 当与去甲基化药物地西他滨或5-氮胞苷联合使用时，显示出令人印象深刻的活性； 然而，在风险细胞遗传学不佳或患有TP53的患者中，结果仍然较为温和。 突变。根据最近的研究结果，将地西他滨的时间表从第1-5天增加到第1-10天 28天周期与改善患者的总体反应和生存率有关-- 冒着细胞遗传学和TP53突变的风险，我们假设同时使用万乃馨和10天 地西他滨将提高疗效和存活率，特别是在高危核型或TP53患者中 突变。我们设计了一项II期试验，将招募四个平行的开放标签队列，每个队列有40名患者 由高龄或复发/难治性疾病的高危AML或MDS患者组成。这个 主要目标是确定综合总体应答率；次要目标包括确定 无病和总存活率，以及高风险核型对反应和存活率的影响。此外, 我们将检验两个分子假说。首先，清除外显子组定义的创始克隆突变 外周血提供了一致和量化的反应终点，绕过了许多来源 患者间反应变异性，万乃馨和地西他滨联合使用将与 与单药地西他滨相比，突变清除的速度和深度都有所提高。确定是否存在 与单一药物相比，去甲基化双联制剂改善了结果，除了大的外，对所有人来说都是一个挑战 随机研究，部分原因是临床混杂因素，如血液稀释抽吸物和计数恢复差 在年龄较大和经过大量预治疗的患者中。这种新的确定反应的方法分离出抗白血病药物 来自其他因素的活跃度，从而提高了研究的统计能力。第二，我们将确定是否 联合应用文思妥拉和地西他滨的疗效与白血病对bcl2活性的依赖或 其他抗细胞凋亡的蛋白质。我们将应用动态BH3分析来确定AML爆炸的相关性 Bcl2、bclxl或mcl1基因上，并将这些结果与应答、生存和突变模式相关联。此外， 我们将对治疗期间和复发时获得的系列骨髓样本进行细胞周期分析。我们会 白血病干细胞亚群和bcl2家族蛋白在原发AML细胞中的表达 与白血病干细胞的对比。这些数据将决定万乃馨和地西他滨联合使用是否会导致 大量干细胞和白血病干细胞种群的消除，以及亚群内的敏感性 与细胞内bcl2家族蛋白的水平相对应。总的来说，这些研究将评估临床 一种新的联合治疗的反应和分子结果，并将确定预后生物标志物和 抗性机制。

PROJECT SUMMARY The outcomes of elderly patients and relapsed/refractory patients with either acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) remain poor. Venetoclax is a selective BCL-2 inhibitor that recently demonstrated impressive activity when combined with hypomethylating agents decitabine or 5-azacitidine; however, outcomes remained more modest among patients with unfavorable risk cytogenetics or with TP53 mutations. Building on recent findings that increasing the schedule of decitabine from days 1-5 to days 1-10 of 28 day cycles was associated with improved overall responses and survival among patients with unfavorable- risk cytogenetics and TP53 mutations, we hypothesize that concomitant use of venetoclax and 10-day decitabine will improve the response and survival rates, especially in patients with high-risk karyotypes or TP53 mutations. We designed a Phase II trial that will enroll four parallel, open-label cohorts, each with 40 patients consisting of high-risk AML or MDS patients, either with advanced age or with relapsed/refractory disease. The primary objective is to determine the composite overall response rate; secondary objectives include determining disease-free and overall survival, and the impact of high-risk karyotypes on response and survival. In addition, two molecular hypotheses will be tested. First, that clearance of exome-defined founding clone mutations from the peripheral blood provides a consistent and quantified response end-point that circumvents many sources of inter-patient response variability, and that combination venetoclax and decitabine will be associated with increased rate and depth of mutation clearance vs. single-agent decitabine. Determining whether a hypomethylating doublet has improved outcomes vs. single-agent has been challenging for all but large randomized studies, partially due to clinical confounders such as hemodilute aspirates and poor count recovery in older and heavily pre-treated patients. This novel approach to response determination isolates anti-leukemic activity from other factors, thus improving statistical power of the study. Second, we will determine whether responses to combination venetoclax and decitabine correlate with leukemic dependence on BCL-2 activity or on other anti-apoptotic proteins. We will apply dynamic BH3 profiling to determine the dependence of AML blasts on BCL-2, BCL-XL or MCL-1 and correlate these results with response, survival, and mutation patterns. Further, we will apply CyTOF analysis to serial bone marrow samples obtained during therapy and at relapse. We will quantify leukemia stem cell subpopulations and the expression of BCL-2 family proteins within bulk AML cells vs. leukemia stem cells. These data will determine whether combination venetoclax and decitabine leads to elimination of both bulk and leukemia stem cell populations, and whether sensitivity within subpopulations corresponds with intracellular levels of BCL-2 family proteins. Collectively, these studies will evaluate clinical responses and molecular outcomes of a novel combination therapy and will identify prognostic biomarkers and resistance mechanisms.