Cardiotoxicity of CPX-351 vs 7+3 in patients with untreated high-risk acute myeloid leukemia.

Abstract

7029 Background: CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in the United States and Europe. While CPX-351 demonstrated improved overall survival and a similar safety profile vs 7+3 in the phase 3 clinical trial (NCT01696084), the safety of CPX-351 related to cardiac function has not been fully described, an important consideration, due to the known cardiotoxicity risk from anthracyclines. This post hoc analysis assessed the impact of CPX-351 vs 7+3 chemotherapy on cardiac impairment in a subset of adults with newly diagnosed high-risk or secondary AML (sAML) from the phase 3 trial. Methods: In the phase 3 trial, 309 patients (60–75 years old; AML according to WHO 2008 criteria) were randomized 1:1 to receive CPX-351 (100 units/m2 on days 1, 3 and 5; days 1 and 3 for second induction) or 7+3 (cytarabine 100 mg/m2/day for 7 days [5 days for second induction] and daunorubicin 60 mg/m2 on days 1–3 [days 1–2 for second induction]). Cardiac impairment was determined by cardiac adverse events (AEs) as well as echocardiogram (ECHO) measures including left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), which were assessed at baseline and two follow-up visits. Results: The study population included 102 patients (CPX-351, n = 57; 7+3, n = 45) with normal baseline LVEF (LVEF > 53%) and at least one post-baseline ECHO measure (LVEF or GLS). Median (min, max) age was 68 (60, 75) years for CPX-351 vs 66 (60, 75) years for 7+3. The mean cumulative dose of daunorubicin while on study was lower for patients receiving CPX-351 vs 7+3 (378 vs 570 mg, respectively). Lower proportions of CPX-351 vs 7+3-treated patients had LVEF < 53% (12% vs 31%) or GLS ≤18% (25% vs 38%) at follow-up 1 or 2. A clinically significant change in LVEF ( > 10% decrease from baseline and LVEF < 53%) or GLS ( > 12% relative decrease from baseline and GLS < 18%) was less common in patients treated with CPX-351 vs 7+3 (9% vs 20% and 21% vs 44%, respectively) at follow-up 1 or 2. The frequency of any cardiac AE by treatment group was similar for both CPX-351 and 7+3 (40% vs 42%). Tachycardia was the most common cardiac AE in CPX-351-treated patients (21% vs 9% in 7+3-treated patients), while atrial fibrillation was the most common cardiac AE in 7+3-treated patients (11% vs 4% in CPX-351-treated patients). Conclusions: The results of this post hoc analysis of data from the phase 3 trial show that CPX-351 is associated with less cardiotoxicity in adults with newly diagnosed high-risk or sAML, when compared with 7+3. The lower mean cumulative doses of daunorubicin while on study with CPX-351 appear to result in better cardiac outcomes with CPX-351 vs 7+3 chemotherapy. Characteristics of CPX-351, such as liposomal delivery, may also contribute to this effect but require further study to confirm this. Clinical trial information: NCT01696084 .