Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML.

Abstract

7000 Background: Older patients with secondary AML have poor outcomes following first-line cytarabine and anthracycline-based treatment. CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio with enhanced efficacy among poor risk AML patients. We report final results from a randomized open-label study of first-line CPX-351 in patients with high-risk sAML (NCT01696084). Methods: Patients 60-75 years of age with untreated AML with a history of prior cytotoxic treatment, antecedent MDS or CMML (+/- prior hypomethylator treatment), or AML with WHO-defined MDS-related cytogenetic abnormalities were eligible. 300 patients were to be randomized 1:1 to CPX-351 (100 units/m2, days 1, 3, 5) or 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy. Endpoints included: overall (OS, 1o) and event free survival (EFS) assessed by stratified log rank analysis, independent blinded assessment of CR+CRi, and 60-day mortality. Patient enrollment was from Dec 2012 to Nov 2014 at 39 US and Canadian sites. Study assumptions included: exponential survival, control median OS=192d, accrual of 135 pt/yr, and analysis after 236 deaths, resulting in 93.7% power to detect a HR=0.635, p=0.05 (2-sided). Results: A total of 309 patients were randomized (153 to CPX-351 + 156 to 7+3) and were well balanced for sex, race, age, performance status, AML-subtype, MDS-related cytogenetics and prior HMA therapy. After minimum follow-up of 13.7 months final analysis began.CPX-351 treatment resulted in superior overall survival (HR=0.69; P=0.005; median OS 9.56 vs. 5.95 months), EFS (HR=0.74; P=0.021), and CR+CRi response (47.7% vs. 33.3%; P=0.016). 60-day mortality favored CPX-351 (13.7% vs. 21.2%). Grade 3-5 AEs were equal (92% vs. 91%) and were similar in frequency and severity in both arms. Similar numbers of patients were transplanted in both arms. Conclusion: CPX-351 treatment significantly improved overall survival, event free survival, and response without an increase in 60-day mortality or AE frequency or severity. CPX-351 should become the standard of care for older patients with secondary AML. Clinical trial information: NCT01696084.