October 31, 2018Journal of Clinical Oncology105 citations
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
Key Result
Early treatment-related cardiotoxicity was associated with significantly worse 5-year event-free survival (HR 1.57) and overall survival (HR 1.59) compared to patients without cardiotoxicity.
Study Design
Type
Cohort (n=1,022)
Multicenter
Yes
Structured PICO
Does early treatment-related cardiotoxicity reduce event-free and overall survival in pediatric patients with acute myeloid leukemia?
P
Population
1,022 pediatric and young adult patients (younger than 30 years) with acute myeloid leukemia treated in the AAML0531 trial, followed for a median of 6.6 years.
E
Exposure
Early-onset cardiotoxicity (defined as grade 2 or higher left ventricular systolic dysfunction)
C
Comparator
Patients without documented cardiotoxicity
O
Outcome
Event-free survival (EFS) and overall survival (OS)hard clinical
Early treatment-related cardiotoxicity in pediatric acute myeloid leukemia is associated with significantly decreased event-free and overall survival, highlighting the need for cardioprotective strategies.
Main Result
Hazard Ratio: 1.57 (95% CI 1.16–2.14)
p-value: p=0.004
Limitations
- Moderate noncompliance with cardiac monitoring over follow-up
- Reliance on passive adverse event reporting without central echocardiogram review
- Lack of detailed information on treatment modifications, cardiovascular management, and salvage therapies
- Dexrazoxane use was not captured
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.