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

了解 IDH 突变 AML 的治疗反应模式和治疗耐药性

• 批准号: 10446974
• 负责人: Ann-Kathrin Eisfeld
• 金额: $ 66.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446974
• 关键词: Address; Adult Acute Myeloblastic Leukemia; Age; Apoptosis; Automobile Driving; Biological; Cancer Center; Cell Differentiation process; Cells; Characteristics; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Clonal Evolution; Collaborations; Collection; Combined Modality Therapy; Complement; Correlative Study; Cytotoxic Chemotherapy; DNA; Data; Data Analyses; Decision Making; Diagnosis; Disease; Disease Progression; Disease remission; Dissection; Drug resistance; Enzymes; Epigenetic Process; Evolution; FDA approved; Future; Gene Expression; Gene Mutation; Genetic; Genetic Anticipation; Genome; Genomics; Genotype; Goals; Hematopoietic; Histones; Hypermethylation; Impairment; Investigation; Mediating; Methylation; Modality; Modeling; Modernization; Molecular; Molecular Abnormality; Molecular Profiling; Mutate; Mutation; Neoadjuvant Therapy; Newly Diagnosed; Oncology; Outcome; Outcome Study; Pathway interactions; Patients; Pattern; Prediction of Response to Therapy; Production; Prognosis; Prospective cohort; Regimen; Relapse; Research Personnel; Residual Tumors; Resistance; Retrospective cohort; Role; Sampling; Therapeutic; Treatment Efficacy; Treatment Failure; Treatment Protocols; Treatment outcome; aged; analytical method; base; chemotherapy; clinical practice; clinically relevant; cohort; compare effectiveness; cytotoxic; design; drug mechanism; epigenome; exome sequencing; experience; head-to-head comparison; improved outcome; in vivo; individual patient; individualized medicine; inhibitor; insight; leukemia; liquid biopsy; mouse model; mutant; novel; personalized medicine; precision medicine; predicting response; predictive marker; programs; response; risk stratification; sample collection; small molecule; small molecule inhibitor; targeted agent; targeted treatment; therapy design; therapy resistant; transcriptome sequencing; translational study; treatment choice; treatment response

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.

摘要