Dexrazoxane Prevents Anthracycline-Related Cardiotoxicity in Childhood AML

Richard Aplenc, MD, PhD

New data from researchers at the Children’s Hospital of Philadelphia (CHOP) suggests use of dexrazoxane could provide some much-needed cardiovascular protection to pediatric patients undergoing chemotherapy for acute myeloid leukemia (AML).

With up to 12% of AML patients experiencing left ventricular systolic dysfunction (LVSD) and results indicating dexrazoxane preserves cardiac function, results of the study could have an immediate impact on real-world treatment algorithms for pediatric patients with AML.

"This study provides important evidence that using dexrazoxane helps prevent heart damage in children undergoing treatment for AML," said lead investigator Richard Aplenc, MD, PhD, professor of pediatrics in the Department of Pediatrics and core faculty member of the Center for Pediatric Clinical Effectiveness at CHOP, in a statement from CHOP. "These results have arguably changed the standard of care for pediatric AML treatment."

With LVSD in AML patients associated with an increase in mortality, Aplenc and a team of colleagues sought to determine whether use of dexrazoxane, which interferes with iron-mediated free radical formation and cell death caused by anthracyclines, could mediate the risk of LVSD. The current study was part of the Children’s Oncology Group trial AAML1031 and examined a multicenter cohort of 1014 pediatric patients with AML without high allelic ratio FLT3/ITD.

Briefly, the study protocol called for anthracyclines to be withheld from patients if there was evidence of LVSD, which was defined as shortening fraction less than 28% or ejection fraction less than 55%. The current analysis sought to assess the occurrence of LVSD, 5-year event-free survival, overall survival, treatment-related mortality, and trends in ejection fraction and shortening fraction by dexrazoxane exposure.

Of the 1014 patients included in AAML1031, which was the most recent AML trial from the Children’s Oncology Group, 96 were exposed to dexrazoxane at every anthracycline cycle course while the remaining 918 were never exposed. Investigators noted sex, age, race, presenting white blood cell count, risk group, treatment arm, and compliance with cardiac monitoring were similar for those exposed to dexrazoxane-exposed and unexposed patients.

Upon analysis, results indicated patients exposed to dexrazoxane had significantly smaller declines of ejection fraction and shortening fraction compared to unexposed patients across courses. Results also indicated a lower risk of LVSD among patients exposed to dexrazoxane.

Results suggested 5-year event-free survival rates and overall survival rates (65.0% v 61.9%; P=.613) were similar between the 2 groups while also highlighting lower treatment-related mortality in patients exposed to dexrazoxane (5.7% v 12.7%; P=.068).

The aforementioned statement from CHOP noted an upcoming trial—COG Phase 3 AML trial—will require dexrazoxane use for all patients receiving standard chemotherapy based on the results of this study.

"This suggests that dexrazoxane may directly prevent acute, severe cardiac events that contribute to early deaths. Additional research to understand the underlying biology of anthracycline-associated cardiotoxicity and effective interventions will improve both the cardiovascular and oncologic outcomes for children with cancer,” said investigator Kelly Getz, PhD, MPH, assistant professor of epidemiology in the University of Pennsylvania Perelman School of Medicine's Department of Biostatistics, Epidemiology, and Informatics, in the statement.

This study, “Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children’s Oncology Group,” was published in the Journal of Clinical Oncology.