General AML

Treatment-related cardiotoxicity in pediatric patients with acute myeloid leukemia treated in the AAML0531 clinical trial

Outcomes of pediatric patients with acute myeloid leukemia (AML) have significantly improved over the past several decades with overall survival (OS) rates now approaching 70%.1 Despite this improvement, anthracycline-associated cardiotoxicity, including left ventricular systolic dysfunction (LVSD), remains a serious risk for this patient population. Kelly D. Getz, PhD, of the Perelman School of Medicine, University of Pennsylvania, PA, USA, and colleagues analyzed pediatric patients with AML treated as part of COG AAML0531 trial in order to evaluate the independent effects of early-onset cardiotoxicity on event-free survival (EFS) or OS.2 The study was published in the Journal of Clinical Oncology on 1 January 2019.

The AAML0531 trial enrolled patients aged 30 or younger who were treated with intravenous infusions of daunorubicin and mitoxantrone. Cardiotoxicity was defined as grade 2 or higher LVSD on the basis of Common Terminology Criteria for Adverse Events definitions. Adverse events during a 5-year follow-up were monitored among 1,022 pediatric patients with AML.

Key findings
  • About 12% of patients had cardiotoxicity reported; 71% of these events were first observed during on-protocol therapy
  • The median time to cardiotoxicity was 4.3 months
  • On-protocol cardiotoxicity was significantly correlated with subsequent off-protocol toxicity
  • Patients with documented cardiotoxicity had significantly worse EFS: HR = 1.6 (95% CI, 1.2–2.1), P = 0.004
  • Patients with documented cardiotoxicity had significantly inferior OS: HR = 1.6; 95% CI, 1.2–2.2), P = 0.005
  • Effects on EFS were similar for those with infection-associated LVSD and those with LVSD without infection
  • Reductions in OS were significantly worse for cardiotoxicity not associated with infection than those with infection-associated cardiotoxicity: HR = 1.7 (95% CI, 1.2–2.5), P = 0.004 vs HR = 1.3 (95% CI, 0.7–2.4), P = 0.387\

The study authors concluded that “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.”

These findings are important to better understand cardiotoxicity risk factors and to reduce anthracycline-induced left ventricular dysfunction in children with AML. This significant decrease in EFS and its effect on OS highlights the necessity of prospective clinical trials to evaluate prophylactic interventions.

References
  1. Faulk K. et al. Overview of therapy and strategies for optimizing outcomes in de novo pediatric acute leukemia. Paediatr Drugs. 2014 Jun;16(3):213-27. DOI: 1007/s40272-014-0067-3.
  2. Getz KD. et al. 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. J Clin Oncol.2019 Jan 1;37(1):12-21. DOI: 1200/JCO.18.00313. Epub 2018 Oct 31.
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