Abstract
PurposeDaunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization.MethodsTwenty-six adults with acute leukemia were treated with CPX-351 for 1–2 induction cycles and ≤ 4 consolidation cycles. The primary endpoint was mean change in QTcF from baseline.ResultsMean QTcF changes were < 10 ms at all time points. No clinically meaningful effects on heart rate, QRS interval, PR interval, or QTcB were observed. Estimated mean half-lives for total cytarabine and daunorubicin were > 30 h. Thirteen (50%) patients achieved remission. The most common adverse events were febrile neutropenia, fatigue, and nausea.ConclusionsThe cytarabine and daunorubicin in CPX-351 liposomes were metabolized and excreted similarly to conventional formulation; however, plasma pharmacokinetics were altered. CPX-351 did not prolong the QT interval, suggesting that CPX-351 may induce less cardiotoxicity than previously reported for conventional daunorubicin.Trial registrationClinicaltrials.gov identifier: NCT02238925.
Highlights
The combination of cytarabine plus an anthracycline, such as daunorubicin (7 + 3 regimen), has been a standard of care for acute myeloid leukemia (AML) induction for decades [1]
The 7 + 3 regimen has historically been restricted to patients with adequate cardiac function due to the risks associated with conventional cytarabine and daunorubicin formulations
Earlier reports suggested no correlation between acute and chronic cardiotoxicity, more recent research found that acute cardiotoxicity, such as QT prolongation, can be used to gauge anthracycline-induced cardiac damage [26, 27]
Summary
The combination of cytarabine plus an anthracycline, such as daunorubicin (7 + 3 regimen), has been a standard of care for acute myeloid leukemia (AML) induction for decades [1]. In the pivotal phase 3 study of older patients with newly diagnosed, high-risk/secondary AML, CPX-351 significantly prolonged median overall survival versus 7 + 3 (9.56 vs 5.95 months, respectively; HR = 0.69; 1-sided P = 0.003). Anthracyclines, including daunorubicin, can induce acute and chronic cardiotoxicity, such as QT interval prolongation and left ventricular dysfunction [15, 17,18,19,20]. In addition to its benefit in prolonging survival and remission rates compared with conventional 7 + 3, CPX-351 might attenuate the risk of potentially fatal anthracycline-induced cardiotoxicity. The International Council on Harmonisation guidelines recommend evaluating the effects of new therapies on the QT interval [23] This phase 2 study was designed to assess the effects of CPX-351 on cardiac repolarization and further characterize the CPX-351 pharmacokinetic profile in patients with acute leukemia
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