Grant Number:	1R03CA301367-01A1 Interpret this number
Primary Investigator:	Janitz, Amanda
Organization:	University Of Oklahoma Hlth Sciences Ctr
Project Title:	Evaluating Inherited Genetic Variation and Outcome Among Children Andadolescents Treated for Acute Myeloid Leukemia
Fiscal Year:	2026

Project Summary/Abstract Acute myeloid leukemia (AML) is a rare childhood malignancy that represents 15-20% of all leukemia diagnoses among children. Although survival rates among patients diagnosed with pediatric AML have improved over the past several decades (from <30% in the 1970s to approximately 70% today), overall survival still lags childhood leukemia overall (87%). Furthermore, contemporary curative therapy for pediatric AML is associated with profound acute and long-term toxicity, including an increased risk of cardiovascular events. In fact, nearly 50% of patients demonstrate evidence of cardiac dysfunction during treatment and an estimated 12% of survivors will develop premature heart failure. Our long-term goal is to improve outcomes among children and adolescents with AML through an improved understanding of the genetic etiology of adverse outcomes. While well- established prognostic factors for AML include both clinical and disease features, important gaps remain unanswered: 1) to what extent does inherited genetic variation contribute to variability in disease outcomes, and 2) does development of a polygenic risk score improve our ability to identify patients at risk of significant cardiotoxicity. This application pursues the central hypothesis that germline genetic variation in critical genetic pathways contributes significantly to individual susceptibility to unfavorable response to contemporary AML therapy. To evaluate this hypothesis, this study proposes two aims: 1) identify germline genetic variation in pharmacogenetics and cancer predisposition genes associated with AML overall and event-free survival, and 2) Develop and optimize a multi-ancestry polygenic risk score for treatment-associated cardiotoxicity in pediatric patients with AML. To accomplish these aims, this proposal leverages Gabriella Miller Kids First germline whole genome sequencing data generated on 1,126 AML patients and rich phenotype and outcomes data collected on these patients as part of the Children’s Oncology Group AAML1031 clinical trial. The investigative team is uniquely positioned to accomplish the proposed study. This application has the potential to advance our understanding of how germline genetic variation contributes to differences in AML survival and treatment- associated toxicity among children and adolescents. Ultimately, this work may guide clinical decision making regarding available treatment modalities, inform the delivery of targeted therapies, and assist with genetic counseling and screening strategies for patients and their families.





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