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 cu...