Early Treatment-Related Cardiotoxicity and Subsequent Outcomes in Pediatric Acute Myeloid Leukemia: an Assessment of Development, Progression and Mitigation

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PROJECT SUMMARY/ABSTRACT Cardiac toxicity is a common consequence of the intensive anthracycline-based chemotherapy regimens responsible for dramatic improvements in childhood cancer cure rates. Given that treatment for pediatric acute myeloid leukemia (AML) involves the highest cumulative doses of anthracyclines among all pediatric cancers, these patients are at particularly high risk for the associated short- and long-term cardiac morbidity and mortality. A recent study of de novo pediatric AML therapy demonstrated a 12% incidence of left ventricular systolic dysfunction (LVSD; ejection fraction < 50%), within one year of treatment. Those with LVSD had a dramatic reduction in both event free and overall survival (OS), likely related to anthracycline dose reduction. Overall, these data suggest that the prevention, early detection and mitigation of cardiotoxicity is critical to the long-term survival of patients. Unfortunately, there is a dearth of information on the natural history of cardiotoxicity in pediatric AML, meaningful predictors of its occurrence, and the effectiveness of cardiac- directed pharmacotherapies in preventing or treating the toxicity. This knowledge gap is likely the result of the limited relevant data captured as part of cooperative group oncology trials. The overarching goal of this proposal is to better understand the development of cardiotoxicity and better predict its occurrence, in order to improve the outcomes of children with AML. By leveraging three unique data resources, namely Children’s Oncology Group clinical trial data, the Pediatric Health Information System database, and granular electronic medical record data from Children’s Hospital of Philadelphia (CHOP) and Texas Children’s Hospital, this study will address important questions across the cardiotoxicity risk continuum. The specific aims are to (1) identify distinct trajectories of cardiotoxicity progression and resolution and their clinical and demographic correlates, (2) compare the direct and indirect effects of cardiac-directed interventions on relapse risk and OS, and (3) determine the prevalence of cardiovascular (CV) comorbidities and their value in predicting cardiotoxicity in pediatric patients initiating AML treatment. With the support of this K01 award, the applicant, Kelly D. Getz, PhD, MPH, will acquire training and mentorship in CV epidemiology, cardio-oncology research, and advanced longitudinal and life course statistical methods. To complete these training goals, Dr. Getz assembled a supportive, multi-disciplinary mentoring team led by her primary mentor, Richard Aplenc, MD, PhD. Her training plan addresses the desired competencies through coursework, workshops, conferences, clinical observation, and directed readings. She will benefit from the outstanding depth of resources and opportunities at CHOP and the University of Pennsylvania. Her long-term career goal is to utilize existing data resources in creative ways to enable epidemiology studies that will impact clinical practice and improve both CV and oncologic outcomes for children with cancer.