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The who and why of anthracycline-related cardiotoxicity in childhood cancer survivors

Smita Bhatia

Smita Bhatia


The University of Alabama at Birmingham

Project Term: July 1, 2018 - June 30, 2021

Childhood cancer survivors are at high risk of dose-dependent anthracycline-related cardiotoxicity. Inter-patient variability in this risk suggests the moderating role of genetic predisposition. This application breaks new ground by harnessing and merging novel concepts from the field of molecular biology and cancer survivorship to understand the pathogenesis of anthracycline-related cardiotoxicity and identify individuals by their personal risk of anthracycline-related cardiotoxicity.

Lay Abstract

Anthracycline chemotherapies are critical for treating children with leukemia and lymphoma. However, one of the most widely-recognized side-effects of anthracycline chemotherapy is the risk of heart failure. Childhood cancer survivors are at a 5- to 15-fold higher risk of heart failure when compared with the general population; less than 50% survive 5 years from diagnosis of heart failure. However, the risk of heart failure is not borne equally by all; thus while some develop heart failure at low-dose exposure to anthracyclines, others escape even after receiving very high doses; this observation suggests that genetic predisposition to how an individual handles anthracyclines and how the heart responds to the anthracyclines may be at play. Indeed, we and others have shown an association between certain genes and heat failure. These observations indicate a critical need to identify children with leukemia or lymphoma at highest risk of heart failure, such that targeted interventions can be instituted. We propose to develop a risk prediction model in childhood leukemia/ lymphoma survivors; this model will include a patient’s genetic make-up, clinical characteristics and treatment exposures. We will replicate the model in independent cohorts of childhood cancer survivors and will then apply the model to newly-diagnosed children with leukemia or lymphoma. These resources present us with an unprecedented opportunity to determine the association of the risk prediction model with: a) relapse of cancer, b) survival, and of course, c) risk of heart failure. Finally, we will determine the molecular basis of anthracycline-related heart failure. Thus, a clinical+genetic risk prediction model will allow identification of children with leukemia or lymphoma at highest risk for heart failure. This risk prediction model, when applied to newly-diagnosed patients with hematologic malignancies will allow for personalized interventions, thus reducing the burden of morbidity due to heart failure, while optimizing cancer-free survival. Finally, an understanding of the mechanism of anthracycline-related cardiotoxicity will set the stage for future interventions targeting molecular mechanisms of heart failure. The necessary infrastructure for the proposed research will be leveraged to test our hypotheses and take the field of personalized medicine to the clinic in children with hematologic malignancies, by minimizing long-term morbidity, while preserving survival.

Translational Research Program
Grant Subprogram
TRP Basic
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