Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: A Children's Oncology Group report Provisionally Accepted

Kasey J. Leger^1* Michael J. Absalon² Biniyam Demissei³ Amanda M. Smith³ Robert Gerbing⁴ Todd Alonzo^{4, 5} Hari Narayan⁶ Betsy A. Hirsch⁷ Jessica Pollard^{8, 9} Bassem I. Razzouk¹⁰ Kelly D. Getz¹¹ Richard Aplenc¹² E A. Kolb^{13, 14} Bonnie Ky³ Todd Cooper¹

• ¹Division of Pediatric Hematology/Oncology, Seattle Children's Hospital, United States
• ²Department of Pediatrics, Oregon Health Sciences University, United States
• ³Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, United States
• ⁴Children's Oncology Group, United States
• ⁵Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, United States
• ⁶Rady Children's Hospital, University of California, San Diego, United States
• ⁷University of Minnesota Health Sciences, University of Minnesota Medical Center, United States
• ⁸Department of Pediatric Oncology, Dana–Farber Cancer Institute, United States
• ⁹Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, United States
• ¹⁰Peyton Manning Children’s Hospital at St.Vincent, United States
• ¹¹Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, United States
• ¹²Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA, United States
• ¹³Alfred I. duPont Hospital for Children, United States
• ¹⁴Nemours Center for Cancer and Blood Disorders, United States

Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421.Methods: Subjects received 135 units/m²/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/-1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 LVEF with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of >10% to <50%.Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m 2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was < 50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (LVEF -3.3% [-7.8,0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline (baseline hs-cTnT 7.2 [3,10.6]; cTnT 1.80 [0,6.1], p=0.03). NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF.In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).