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

Abstract

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.

Optimizing Cardiovascular Care in Children With Acute Myeloid Leukemia to Improve Cancer-Related Outcomes

“…Overall, there was modest (54%) adherence to protocolmandated echocardiographic evaluations, and the rates were lowest during off-protocol follow-up. 32 As such, the rate of LVSD reported in this study underestimates the true magnitude of risk that may not become apparent until these children enter adulthood. In fact, studies have consistently shown that the echocardiogram obtained in the year after completion of therapy is the most important predictor of future heart failure risk.…”

“…The study that accompanies this article by Getz et al 32 describes the incidence and natural history of LVSD in 1,022 pediatric patients with AML treated in the Children's Oncology Group trial AAML0531 (ClinicalTrials.gov identifier: NCT00372593) and examines the effect of LVSD on their EFS and OS. In the study, approximately 12% of patients developed LVSD over a 5-year follow-up, with greater than 70% of incident events occurring during onprotocol therapy (8% incidence of cardiotoxicity while on protocol).…”

Strategies to prevent anthracycline-induced cardiotoxicity in cancer survivors

“…In fact, for at least the past two decades, anthracycline-induced HF has been a leading co-morbidity in survivors of childhood cancers [40]. In 1022 children with acute myeloid leukemia treated in the Children's Oncology Group trial, 12% experienced cardiotoxicity (grade 2 or higher LV systolic dysfunction) during 5 years of follow-up, with more than 70% of incident events occurring during onprotocol therapy [41]. Both event-free survival (hazard ratio [HR], 1.6, 95% CI, 1.2 to 2.1; P = 0.004) and overall survival (HR, 1.6; 95% CI, 1.2 to 2.2; P = 0.005) were significantly worse in patients with documented cardiotoxicity (defined in this study as resting SF < 24% or EF < 50%).…”

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children’s Oncology Group

“…Doxorubicin is perhaps the most important agent for the treatment of OS [3]. Most protocols use cumulative doses of 375-450 mg/m 2 , which can be associated with cardiotoxicity during treatment, as well as long-term cardiovascular morbidity and early mortality [4,5].…”