Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children's Oncology Group.
PMCID: PMC6354770; DOI: 10.1200/JCO.18.00313
PURPOSE: Late cardiotoxicity after pediatric acute myeloid leukemia therapy causes substantial morbidity and mortality. The impact of early-onset cardiotoxicity on treatment outcomes is less well understood. Thus, we evaluated the risk factors for incident early cardiotoxicity and the impacts of cardiotoxicity on event-free survival (EFS) and overall survival (OS).
METHODS: Cardiotoxicity was ascertained through adverse event monitoring over the course of follow-up among 1,022 pediatric patients with acute myeloid leukemia treated in the Children's Oncology Group trial AAML0531. It was defined as grade 2 or higher left ventricular systolic dysfunction on the basis of Common Terminology Criteria for Adverse Events (version 3) definitions.
RESULTS: Approximately 12% of patients experienced cardiotoxicity over a 5-year follow-up, with more than 70% of incident events occurring during on-protocol therapy. Documented cardiotoxicity during on-protocol therapy was significantly associated with subsequent off-protocol toxicity. Overall, the incidence was higher among noninfants and black patients, and in the setting of a bloodstream infection. Both EFS (hazard ratio [HR], 1.6; 95% CI, 1.2 to 2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2 to 2.2, P = .005) were significantly worse in patients with documented cardiotoxicity. Impacts on EFS were equivalent whether the incident cardiotoxicity event occurred in the absence (HR, 1.6; 95% CI, 1.1 to 2.2; P = .017) or presence of infection (HR, 1.6; 95% CI, 1.0 to 2.7; P = .069) compared with patients without documented cardiotoxicity. However, the reduction in OS was more pronounced for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2 to 2.5; P = .004) than for infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7 to 2.4; P = .387).
CONCLUSION: Early treatment-related cardiotoxicity may be associated with decreased EFS and OS. Cardioprotective strategies are urgently needed to improve relapse risk and both short- and long-term mortality outcomes.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Child; Child, Preschool; Daunorubicin; Disease-Free Survival; Echocardiography; Humans; Incidence; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Mitoxantrone; Proportional Hazards Models; Risk Factors; Survival Rate; Treatment Outcome
Leukemia; AML; children
Getz, K. D., Sung, L., Ky, B., Gerbing, R. B., Leger, K. J., Leahy, A. B., Sack, L., Woods, W. G., Alonzo, T., Gamis, A. S., Aplenc, R. Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children's Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37, 12-21 (2019).