Treatment-Related Cardiotoxicity in Pediatric AML

Pediatric patients with acute myeloid leukemia (AML) who experienced early treatment-related cardiotoxicity may have worse event-free survival and overall survival (OS), according to the results of the Children’s Oncology Group AAML0531 trial.

More than one in 10 patients experienced cardiotoxicity during a 5-year follow-up and of these, more than 70% of incident events happened during on-protocol therapy. Those patients with cardiotoxicity had significantly worse event-free and OS.

“Thus, efforts to improve outcomes for children with AML must include prevention and mitigation of on-protocol cardiotoxicity,” Kelly D. Getz, PhD, of the University of Pennsylvania, and colleagues wrote in The Journal of Clinical Oncology. “Such interventions may not only mitigate the impact of early cardiotoxicity but also late cardiotoxicity, which has been shown by multiple investigators to be the leading cause of late morbidity and non-relapse–related mortality in pediatric cancer survivors.”

The study looked at adverse events occurring in 1,022 pediatric patients with AML treated as part of COG AAML0531. This study enrolled patients aged 30 or younger and treated them with intravenous infusions of daunorubicin and mitoxantrone. Cardiotoxicity was defined as grade 2 or higher left ventricular systolic dysfunction (LVSD) on the basis of Common Terminology Criteria for Adverse Events definitions.

About 12% of patients had cardiotoxicity reported during a 5-year follow-up, and 71% of these events were first documented during on-protocol therapy. The median time to cardiotoxicity was 4.3 months. Documented on-protocol cardiotoxicity was significantly associated with subsequent off-protocol toxicity. Incidence of cardiotoxicity was higher among non-infants and black patients, and in the setting of bloodstream infections.

Patients with documented cardiotoxicity had significantly worse event-free survival (hazard ratio [HR], 1.6; 95% CI, 1.2–2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2–2.2; P = .005). Effects on event-free survival were similar for those with infection-associated LVSD and those with LVSD without infection.

Reductions in OS, however, were significantly worse for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2–2.5; P = .004) than those with infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7–2.4; P = .387).

“This dramatic decrease in event-free survival and resulting decrease in overall survival underscore the need to understand cardiotoxicity risk factors and to develop effective prevention strategies,” the researchers wrote.

Commenting on the results of the study, Steven E. Lipshultz, MD, FAAP, FAHA, Conger Goodyear Professor and chair of pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, told Cancer Network that “the ability to help or harm children is real based on an understanding of this data and its implications.”

David Freyer, DO, director of survivorship and supportive care program at of the Children's Hospital of Los Angeles also commented on the study.

"This is an important study that adds new information in a large sample of high-risk patients about early predictors of long-term anthracycline-induced left ventricular dysfunction. It builds on what is already known about this problem and strengthens the case for prioritizing prospective clinical trials to study interventions for preventing this problem," said Freyer.