In a study reported in the Journal of Clinical Oncology, Getz et al found that use of dexrazoxane was associated with preservation of cardiac function in pediatric patients receiving front-line treatment for acute myeloid leukemia (AML) and resulted in no adverse effects on treatment outcomes.
As noted by the investigators, anthracyclines generate iron-mediated free radicals when metabolized by mitochondria, triggering myocardial cell death and left-ventricular systolic dysfunction. By interfering with iron-mediated free radical formation and causing rapid degradation of topoisomerase IIb, dexrazoxane acts to reduce anthracycline-associated cardiotoxicity.
“Dexrazoxane preserved cardiac function without compromising event-free and overall survival or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during front-line treatment of pediatric AML.”— Getz et al
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Study Details
The study involved pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children’s Oncology Group trial AAML1031 between 2011 and 2016, with treatment regimens including anthracyclines, daunorubicin, and mitoxantrone. Dexrazoxane was administered at the discretion of treating physicians, and its use was documented at each course.
Ejection fraction and shortening fraction were recorded after each course and at regular follow-up intervals. Anthracyclines were to be withheld for evidence of left-ventricular systolic dysfunction, defined as shortening fraction < 28% or ejection fraction < 55%.
Key Findings
Median follow-up was 3.5 years. Among 1,014 patients included in the analyses, 96 were exposed to dexrazoxane at every anthracycline course and 918 were never exposed. Sex, age, race, presenting white blood cell count, risk group, treatment arm, and compliance with cardiac monitoring were similar between dexrazoxane-exposed and -unexposed patients.
Longitudinal trends showed that dexrazoxane-exposed patients had significantly smaller ejection fraction (P = .005) and shortening fraction (P < .001) declines vs unexposed patients across treatment courses.
Overall, risk for left-ventricular systolic dysfunction was 26.5% among exposed patients vs 42.2% among unexposed patients (hazard ratio [HR] = 0.55, P = .009), with risk of 11% vs 23% (HR = 0.40, P = .011) for grade ≥ 2 left-ventricular systolic dysfunction and 3.8% vs 8.5% (HR = 0.30, P = .094) for grade ≥ 3 left-ventricular systolic dysfunction.
At 5 years, event-free survival was 49.0% among dexrazoxane-exposed patients vs 45.1% among dexrazoxane-unexposed patients (P = .534) and overall survival was 65.0% vs 61.9% (P = .613). A nonsignificantly lower rate of treatment-related mortality was observed among patients receiving dexrazoxane (5.7% vs 12.7%, P = .068).
Noncardiac toxicity was similar in dexrazoxane-exposed and -unexposed patients. No differences in course length, durations of neutropenia or hospitalization, intensive care unit admissions, or rates of mucositis or bloodstream infection were observed according to dexrazoxane exposure status.
The investigators concluded, “Dexrazoxane preserved cardiac function without compromising event-free and overall survival or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.”
Kelly D. Getz, PhD, MPH, of Perelman School of Medicine, University of Pennsylvania, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute and St. Baldrick’s Foundation. For full disclosures of the study authors, visit ascopubs.org.
