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

使用 BCL-2 抑制剂 Venetoclax 和优化的 10 天地西他滨方案靶向高危 AML 和 MDS 中的细胞凋亡

• 批准号: 10415997
• 负责人: Marina Y Konopleva
• 金额: $ 9.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-17 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415997
• 关键词: Acute Myelocytic Leukemia; Apoptosis; Apoptotic; Aspirate substance; Azacitidine; BCL2 gene; BCL2L1 gene; Bone Marrow; Categories; Cells; Clinical; Combined Modality Therapy; Cytogenetics; Data; Decitabine; Dependence; Disease; Dysmyelopoietic Syndromes; Elderly; Enrollment; Family; Family member; Futility; Future; Goals; Hematologic Neoplasms; Hematology; Institution; Leukemic Cell; MCL1 gene; Mass Spectrum Analysis; Molecular; Molecular Analysis; Monitor; Morphology; Mutate; Mutation; Outcome; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phase II Clinical Trials; Prognosis; Prognostic Marker; Protein Family; Proteins; Protocols documentation; Randomized; Recovery; Refractory; Refractory Disease; Regimen; Relapse; Resistance; Risk; Safety; Sampling; Schedule; Source; Stem cell transplant; Subgroup; Surrogate Endpoint; Survival Rate; TP53 gene; Testing; Therapeutic; Toxic effect; Treatment-related toxicity; Variant; acute myeloid leukemia cell; antileukemic activity; base; clinically significant; cohort; design; exome; exome sequencing; high risk; improved; improved outcome; inhibitor; leukemia; leukemic stem cell; novel; novel strategies; older patient; open label; patient response; peripheral blood; phase 2 study; phase II trial; resistance mechanism; response; small molecule inhibitor; stem cell population

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.

项目概要 老年患者和患有急性髓系白血病 (AML) 或复发/难治性患者的结局 骨髓增生异常综合征（MDS）仍然很差。 Venetoclax 是一种选择性 BCL-2 抑制剂，最近 与低甲基化药物地西他滨或 5-阿扎胞苷联合使用时表现出令人印象深刻的活性； 然而，在具有不利的风险细胞遗传学或 TP53 的患者中，结果仍然较为温和 突变。根据最近的研究结果，将地西他滨的服药时间从第 1-5 天增加到第 1-10 天 28 天的周期与改善不良患者的总体反应和生存相关 风险细胞遗传学和 TP53 突变，我们假设同时使用 Venetoclax 和 10 天 地西他滨将提高缓解率和生存率，特别是对于具有高风险核型或 TP53 的患者 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 由高危 AML 或 MDS 患者组成，这些患者要么是高龄患者，要么是患有复发/难治性疾病的患者。这 主要目标是确定综合总体缓解率；次要目标包括确定 无病生存和总体生存，以及高风险核型对反应和生存的影响。此外， 将测试两个分子假设。首先，清除外显子组定义的创始克隆突变 外周血提供了一致且量化的反应终点，规避了许多来源 患者间的反应变异性，以及维奈托克和地西他滨的组合将与 与单药地西他滨相比，突变清除率和深度增加。确定是否 与单药相比，低甲基化双药可以改善结果，但对除大公司以外的所有人来说一直是一个挑战 随机研究，部分原因是血液稀释抽吸物和计数恢复不良等临床混杂因素 在老年和接受过大量治疗的患者中。这种确定反应的新方法分离出抗白血病药物 其他因素的活动，从而提高研究的统计能力。其次，我们要判断是否 对 Venetoclax 和地西他滨组合的反应与白血病对 BCL-2 活性的依赖相关，或 作用于其他抗凋亡蛋白。我们将应用动态 BH3 分析来确定 AML 原始细胞的依赖性 BCL-2、BCL-XL 或 MCL-1 并将这些结果与反应、生存和突变模式相关联。更远， 我们将对治疗期间和复发时获得的连续骨髓样本应用 CyTOF 分析。我们将 量化大量 AML 细胞中的白血病干细胞亚群和 BCL-2 家族蛋白的表达 与白血病干细胞相比。这些数据将确定维奈托克和地西他滨的组合是否会导致 消除大量干细胞和白血病干细胞群，以及亚群内的敏感性是否 与 BCL-2 家族蛋白的细胞内水平相对应。总的来说，这些研究将评估临床 新型联合疗法的反应和分子结果，并将确定预后生物标志物和 抵抗机制。