<p>Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize cancer survival. Unfortunately, high-dose anthracyclines are associated with a significant risk of cardiotoxicity, which may result in early and/or long-term left ventricular systolic dysfunction and heart failure. Moreover, the development of cardiotoxicity during pediatric AML therapy is associated with lower event-free and overall survival, which may be partially attributable to incomplete anthracycline delivery. A combined strategy of primary cardioprotection and close cardiac monitoring can maximize chemotherapy delivery while reducing the toxicity of intensive AML therapy. Primary cardioprotection using dexrazoxane reduces short-term cardiotoxicity without compromising cancer survival. Liposomal anthracycline formulations, which are under active investigation, have the potential to mitigate cardiotoxicity while also improving antitumor efficacy. Primary cardioprotective strategies may reduce but not eliminate the risk of cardiotoxicity; therefore, close cardiac monitoring is also needed. Standard cardiac monitoring consists of serial echocardiographic assessments for left ventricular ejection fraction decline. Global longitudinal strain has prognostic utility in cancer therapy-related cardiotoxicity and may be used as an adjunct assessment. Additional cardioprotective measures should be considered in response to significant cardiotoxicity; these include cardiac remodeling medications to support cardiac recovery and anthracycline dose interruption and/or regimen modifications. However, the withholding of anthracyclines should be limited to avoid compromising cancer survival. A careful approach to cardioprotection during AML therapy is critical to maximize the efficacy of leukemia treatment while minimizing the short- and long-term risks of cardiotoxicity.</p>

<p><strong>PURPOSE: </strong>Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy.</p>

<p><strong>PATIENTS AND METHODS: </strong>Children &gt; 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m/dose on days 1-5; cytarabine 2,000 mg/m/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count &gt; 500/µL]). Response was assessed after each cycle.</p>

<p><strong>RESULTS: </strong>Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT.</p>

<p><strong>CONCLUSION: </strong>The RP2D of CPX-351 is 135 units/m/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.</p>

<p><strong>PURPOSE: </strong>To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.</p>

<p><strong>PATIENTS AND METHODS: </strong>This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF &lt; 28% or EF &lt; 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.</p>

<p><strong>RESULTS: </strong>A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% 45.1%; = .534) and OS (65.0% 61.9%; = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% 12.7%; = .068).</p>

<p><strong>CONCLUSION: </strong>Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.</p>

<p><strong>PURPOSE: </strong>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).</p>

<p><strong>METHODS: </strong>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.</p>

<p><strong>RESULTS: </strong>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).</p>

<p><strong>CONCLUSION: </strong>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.</p>