Anthracycline-Induced Cardiac Toxicity in Pediatric Acute Myeloid Leukemia
Background
Acute myeloid leukemia (AML) is the most life-threatening form of leukemia requiring the most intensive treatment. While advances in its treatment have improved survival, chemotherapy exposure results in significant side effects. One type of drug, anthracyclines, increases the risk for heart complications.
Anthracycline-induced cardiac toxicity starts with heart cell injury and worsens over time to overt heart disease and heart failure. Therefore, efforts to improve the long-term cardiovascular health and mortality among AML survivors should be directed at early detection and prevention of cardiotoxicity. However, there are little data evaluating the factors that increase the risk for early-onset anthracycline-associated cardiac toxicity and its potential resolution in pediatric AML. Additionally, assessments of drugs such as dexrazoxane that might protect the heart from the damage cause by anthracyclines generally have not included AML patients.
The typical measures used to monitor heart function in childhood cancer may not detect injury until a serious amount of irreversible damage to the heart has taken place. Therefore identifying measures of cardiac function that might be early indicators of damage is important in order to prevent permanent cardiac dysfunction and improve the therapeutic benefit of cardio-protective drugs.
Project Goal:
Therefore the proposed project aims to identify demographic and clinical correlates of early cardiotoxicity and to evaluate myocardial strain and strain rate as early sensitive markers for later dysfunction in an effort to improve the detection of high-risk patients. We also aim to assess the potential utility of dexrazoxane as a cardioprotective intervention in pediatric AML.
Project Update 2018
Through the analyses completed during this first year, we found that more AML patients may experience cardiac toxicity than we previously appreciated. Furthermore, we found that patients treated with a cardio-protective medication, dexrazoxane, were much less likely to experience treatment-related cardiac toxicity than those who are not exposed to dexrazoxane. Additionally, our results suggest that treatment with dexrazoxane may lead to improved event-free and overall survival, potentially through the avoidance of the anthracycline dose modifications that occur when subclinical declines in heart function are detected during AML treatment. We identified subpopulations who may be at especially high risk for cardiac toxicity. We also made progress in developing a CHOP AML cohort within which we will be able to evaluate newer measurements of heart function in an attempt to identify cardiac toxicity earlier.
Project Update 2019
Through the analyses completed during the first two years of funding, we found that nearly 40% of patients experience declines in left ventricular systolic dysfunction of sufficient magnitude to warrant chemotherapy modifications per the COG AAML1031 protocol, a rate larger than previously appreciated. Of these, 19% suffered life-threatening severe toxicity. We identified subpopulations who may be at especially high risk for cardiac toxicity overall and found that there were distinct risk factors for infection-associated toxicity (i.e., overweight/obesity, bortezomib exposure) and toxicity not associated with infection (i.e., low-risk disease). Furthermore, we found that patients treated with the cardio-protective medication, dexrazoxane, were much less likely to experience treatment-related cardiac toxicity, particularly non-infection associated toxicity, then those who are not exposed to dexrazoxane. Additionally, our results suggest that treatment with dexrazoxane protects against treatment-related mortality. We also made progress in developing a CHOP AML cohort within which we will be able to evaluate newer measurements of heart function in an attempt to identify cardiac toxicity earlier.
