Understanding Treatment Response Patterns And Therapy Resistance In IDH-Mutant AML

摘要 AML中IDH 1和IDH 2突变的发现，以及由此产生的IDH 1和IDH 2突变的伴随功能意义， 这些突变酶的新形态活性导致FDA批准的靶向疗法。同样， 由于AML基因组中IDH突变导致的甲基化变化已经迎来了治疗 联合维奈托克和低甲基化药物的治疗方案。在这种情况下，传统的化疗 方案也适用于治疗的主要诊断，所有三个可用的结果数据 治疗方法现在应该提供预测反应的明确指标， 方法.然而，由于缺乏直接的比较研究，对于哪种治疗选择没有指导 将在IDH突变患者中提供最佳响应。此外，关于人口的重要性的新数据显示， 对不同药物反应的生物学背景，包括共存的基因突变和患者年龄， 需要系统解决的其他问题，以便为患者提供最佳治疗。 为了解决这一迫在眉睫的问题，并为约20%的患者提供数据驱动的治疗决策支持， 对于携带IDH突变的AML患者，我们提出了一项精心设计的转化研究： 为了直接比较IDH导向和非IDH导向靶向治疗的反应，我们设计了第一个 针对老年人和不适合IDH突变患者的头对头比较试验。这项迟来的研究将提供 关于治疗反应的信息，以及对最佳治疗顺序的初步了解， 关于共存的分子特征。该试验将通过相关研究进行补充，旨在评估 克隆生长追踪和残留疾病评估在可能的动态治疗中的应用 调整（iDATA试验，Aim 1）。利用来自临床试验联盟的AML患者收集， 肿瘤学，以及我们在美国六个主要癌症中心之间新建立的多中心合作，我们 他们收集了迄今为止最大的930名IDH突变的成人AML患者的队列， 细胞毒性化疗、低甲基化剂或IDH定向或非定向靶向抑制剂。以下 我们在基因组风险分层模型方面的经验，我们有能力识别预测治疗的标志物， 基于治疗类型和基因组背景的反应（目标2）。最后，为了更好地了解阻力， 逃逸机制的靶向和非靶向治疗，我们将利用我们的大型纵向样本 收集提供了不同疾病期间白血病克隆的全面分子表征， 和治疗阶段;包括克隆和亚克隆进化，鉴定克隆特异性改变的细胞 途径和表观遗传变化在每个阶段（目标3）。 我们相信，由一个熟练的调查小组执行的这种全面的方法将改变目前的状况。 临床实践范式向数据驱动和个性化的治疗方法。

ABSTRACT The discovery of IDH1 and IDH2 mutations in AML, and the accompanying functional implications of the resulting neomorphic activity of these mutated enzymes, has resulted in FDA approved targeted therapies. Similarly, the changes brought about in methylation due to IDH mutations in the AML genome have ushered in treatment regimens combining venetoclax with hypomethylating agents. In this setting, where traditional chemotherapy regimens also are applied for treatment of primary diagnoses, the available outcomes data for all three therapeutic approaches should now provide clear metrics of predicted response, given the correct analytical methods. However, given a lack of direct comparison studies, no guidance exists as to which treatment choice will provide best response in IDH-mutated patients. Furthermore, emerging data about the importance of the biologic context on the response to different agents, including co-existing gene mutations and patient age, pose additional questions that need to be systematically addressed in order to provide patients with the best treatment. In order to address this imminent question, and provide data-driven treatment decision support for the ~20% of AML patients harboring IDH mutations, we are proposing a carefully designed, translational study: To directly compare the response of IDH-directed and non-IDH directed targeted therapy, we designed the first head-to-head comparison trial for older and unfit IDH-mutated patients. This long overdue study will provide information about treatment response, as well as first insights into the optimal sequence of treatments, with respect to co-existing molecular features. The trial will be complemented by correlative studies that aim to assess the utility of clonal outgrowth tracking and residual disease assessment for possible dynamic treatment adjustments (iDATA trial, Aim 1). Utilizing the AML patient collection from the Alliance for Clinical Trials in Oncology, as well as our newly established multicenter collaboration between six major US Cancer Centers, we have assembled the thus far largest cohort of 930 IDH-mutated adult AML patients, treated with standard cytotoxic chemotherapy, hypomethylating agents or IDH-directed or non-directed targeted inhibitors. Following our experience in genomic risk stratification models, we are equipped to identify markers predictive of treatment response based on treatment type and genomic context (Aim 2). Lastly, to better understand resistance and escape mechanisms to targeted and non-targeted therapies, we will leverage our large longitudinal specimen collections provide a comprehensive molecular characterization of the leukemic clones during different disease and treatment stages; including clonal and subclonal evolution, identification of clone-specific altered cellular pathways and epigenetic changes at each stage (Aim 3). We are confident that this comprehensive approach, executed by a skilled investigator team will shift current clinical practice paradigms towards data-driven and personalized treatment approaches.