Serial monitoring of circulating cell-free tumor DNA as measured by duplex sequencing in older patients with acute myeloid leukemia who receive azacitidine+venetoclax +/- immune checkpoint blockade

通过双重测序对接受阿扎胞苷维奈托克/免疫检查点阻断的老年急性髓系白血病患者的循环游离肿瘤 DNA 进行连续监测

• 批准号: 10337831
• 负责人: PATRICIA M. LORUSSO
• 金额: $ 10.83万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337831
• 关键词: AML/MDS; Acute Myelocytic Leukemia; Aftercare; Antibodies; Architecture; Automobile Driving; Bar Codes; Biological Markers; Blood specimen; Bone Marrow; Cancer Therapy Evaluation Program; Cells; Characteristics; Clinical; Clinical Data; Clonal Evolution; DNA sequencing; Data; Development; Disease; Disease remission; Drug usage; FLT3 gene; Future; Generations; Genes; Immunoglobulin Class Switching; Immunophenotyping; In Vitro; Induced Mutation; Isocitrate Dehydrogenase; Learning; Leukemic Cell; Malignant neoplasm of ovary; Mission; Multicenter Trials; Mutate; Mutation; Newly Diagnosed; Oligonucleotides; Outcome; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Point Mutation; Population; Process; Production; Resistance; Sampling; Technology; Translating; alternative treatment; base; chemotherapy; clinical efficacy; experience; in vivo; inhibitor/antagonist; insight; interest; leukemia; malignant breast neoplasm; multiple omics; phase 2 study; predicting response; prevent; resistance mechanism; response; response biomarker; single cell sequencing; success; targeted agent; targeted treatment; tool; treatment response; trend

ABSTRACT IDH1 and IDH2 mutations are present in 15 to 20% of newly diagnosed cases of AML. They are associated with the production of the onco-metabolite 2-Hydroxyglutarate and a distinctive clonal landscape. IDH targeted inhibitors have been developed with success over the last decade but primary or secondary resistances remain extremely common. Resistance is driven by a variety of mechanisms including isotype switch, IDH secondary point mutation, acquisition of RTK mutation (such as RAS), or the development of IDH negative clones. Identifying the mechanisms driving resistance in a patient is crucial to be able to develop strategies to prevent and treat progressions. Our group has demonstrated that the presence IDH mutation induces a “BRCAness phenotype” in cells and a sensitivity to PARP inhibitors. These in vitro and in vivo findings were translated in a phase 2 study of Olaparib in IDH mutated AML and MDS (the PRIME study, CTEP #10264). For patients treated with Olaparib, we expect to see a similar pattern of resistance mechanisms as the one seen with IDH inhibitors and in order to optimize our therapies, we need to have a clear picture of the clonal complexity at the different points of the treatment. Conventional “Bulk sequencing” can provide some information but the level of granularity of the data may not be sufficient in all cases. Single cell sequencing may overcome these limitations and the new generation of platforms, such as the Tapestri platform, allow integrated and reliable workflows that can process a large volume of samples. More recently, multi-omics approaches have been developed with concomitant immunophenotyping and this allows to refine even more the results by allowing to focus on different cellular subsets. In this proposal, we use Single Cell DNA Sequencing and multi-omics approach to evaluate the clonal architecture before and during treatment with olaparib. Besides giving us more insights on the mode of action of olaparib, this approach will help us define the mechanisms of primary and secondary resistance to olaparib in this population. Consequently, this will guide our future strategies to overcome these resistances. Second, we will correlate SCS data with clinical response and evaluate if SCS has the potential to be used as a biomarker of response in a multicenter trial setting. 2

抽象的 15% 至 20% 的新诊断 AML 病例中存在 IDH1 和 IDH2 突变。他们是 与肿瘤代谢物 2-羟基戊二酸的产生和独特的克隆景观有关。异丁烯酸脱氢酶 过去十年来，靶向抑制剂已取得成功，但主要或次要耐药性 仍然非常普遍。耐药性由多种机制驱动，包括同型转换、IDH 继发点突变、获得 RTK 突变（例如 RAS）或 IDH 阴性 克隆。确定患者耐药性的机制对于制定策略至关重要 预防和治疗进展。我们的小组已经证明 IDH 突变的存在会诱导 细胞中的“BRCAness 表型”和对 PARP 抑制剂的敏感性。这些体外和体内研究结果 转化为奥拉帕尼治疗 IDH 突变 AML 和 MDS 的 2 期研究（PRIME 研究，CTEP #10264）。为了 对于接受奥拉帕尼治疗的患者，我们预计会看到与接受奥拉帕尼治疗的患者相似的耐药机制模式 IDH 抑制剂，为了优化我们的疗法，我们需要清楚地了解克隆的复杂性 治疗的不同点。传统的“批量测序”可以提供一些信息，但水平 数据的粒度可能不足以满足所有情况。单细胞测序可以克服这些限制 Tapestri 平台等新一代平台可实现集成且可靠的工作流程， 可处理大量样品。最近，多组学方法已被开发出来 伴随免疫表型分析，这可以通过关注不同的结果来进一步完善结果 细胞亚群。 在本提案中，我们使用单细胞 DNA 测序和多组学方法来评估克隆 奥拉帕尼治疗前和治疗期间的结构。除了让我们对作用方式有更多的了解 奥拉帕尼，这种方法将帮助我们定义奥拉帕尼的主要和次要耐药机制 人口。因此，这将指导我们未来克服这些阻力的策略。其次，我们将 将 SCS 数据与临床反应相关联，并评估 SCS 是否有潜力用作以下疾病的生物标志物 多中心试验环境中的反应。 2