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

项目摘要 老年患者和复发/难治性急性髓性白血病（AML）患者或 骨髓增生异常综合征（MDS）仍然很差。维奈托克是一种选择性BCL-2抑制剂， 当与低甲基化剂地西他滨或5-阿扎胞苷组合时显示出令人印象深刻的活性; 然而，在具有不利风险的细胞遗传学或TP 53的患者中， 突变基于最近的发现，将地西他滨的时间表从第1-5天增加到第1-10天， 28天为一个周期与改善的总体反应和生存率相关， 风险细胞遗传学和TP 53突变，我们假设同时使用维奈托克和10天 地西他滨将改善缓解率和生存率，特别是在高危核型或TP患者中53 突变我们设计了一项II期试验，将招募4个平行的开放标签队列，每个队列40名患者 由高风险AML或MDS患者组成，具有高龄或具有复发性/难治性疾病。的 主要目的是确定复合总体缓解率;次要目的包括确定 无病生存期和总生存期，以及高危核型对缓解和生存的影响。此外，本发明还提供了一种方法， 将检验两个分子假设。首先，清除外显子组定义的创建克隆突变， 外周血提供了一致的和定量的反应终点， 患者间反应变异性，以及维奈托克和地西他滨组合将与 与地西他滨单药相比，突变清除率和深度增加。确定是否 与单药相比，低甲基化双药治疗改善了结局， 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不良 在老年和重度预治疗患者中。这种新的反应测定方法分离了抗白血病药物， 活动从其他因素，从而提高统计权力的研究。其次，我们将确定 对维奈托克和地西他滨联合用药的反应与白血病对BCL-2活性的依赖性相关， 对其他抗凋亡蛋白的作用。我们将应用动态BH 3谱来确定AML原始细胞的依赖性， 对BCL-2、BCL-XL或MCL-1的影响，并将这些结果与反应、存活和突变模式相关联。此外，本发明还 我们将对治疗期间和复发时获得的连续骨髓样品进行CyTOF分析。我们将 定量AML细胞中白血病干细胞亚群和BCL-2家族蛋白的表达 vs.白血病干细胞这些数据将确定联合使用维奈托克和地西他滨是否会导致 大量和白血病干细胞群体的消除，以及亚群内的敏感性 与BCL-2家族蛋白的细胞内水平相对应。总体而言，这些研究将评估临床 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， 抵抗机制

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.