Rates of Adverse Events per Patient-Year in a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic drug ratio. Intact CPX-351 liposomes containing the synergistic drug ratio are taken up to a greater extent by leukemia cells versus normal bone marrow cells, have a high retention of drug cargo, and have a long plasma half-life. This randomized, phase 3 study (NCT01696084) evaluated induction with CPX-351 versus conventional cytarabine/daunorubicin (7+3 regimen) in adults aged 60-75 years with newly diagnosed, treatment-related AML or AML with myelodysplasia-related changes. Patients were randomized 1:1 to receive 1 to 2 cycles of induction therapy with CPX-351 (100 units/m² [100 mg/m² cytarabine and 44 mg/m² daunorubicin] on Days 1, 3, and 5 [Days 1 and 3 for second induction]) or conventional 7+3 (cytarabine 100 mg/m²/day for 7 days [5 days for second induction] + daunorubicin 60 mg/m²on Days 1-3 [Days 1-2 for second induction]). Patients with complete response (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Hematopoietic cell transplantation (HCT) was performed at the investigator's discretion; adverse events (AEs) occurring after HCT were not counted in the AE totals for each treatment arm. Here we present a comprehensive analysis of AEs per treatment arm in this clinical trial.

A total of309 patients were enrolled (CPX-351, n = 153; 7+3, n = 156). Baseline characteristics were balanced between arms. Patients treated with CPX-351 had significantly prolonged median overall survival (primary endpoint) compared with the 7+3 arm (9.56 vs 5.95 months, respectively; hazard ratio = 0.69 [95% CI, 0.52, 0.90]; P= 0.005). CPX-351 also resulted in a significantly higher CR+CRi rate versus 7+3 (48% vs 33%, respectively; P= 0.016) and allowed a greater proportion of patients to undergo HCT (34% vs 25%).

Safety analyses included 153 patients who received CPX-351 and 151 patients who received 7+3. The proportions of patients who experienced individual AEs were generally comparable between the CPX-351 and 7+3 treatment arms. However, a greater proportion of patients in the CPX-351 arm received first and second consolidation (32% and 15%, respectively) than in the 7+3 arm (21% and 8%, respectively), resulting in a longer median duration of the treatment phase with CPX-351 (62 days) compared with the 7+3 arm (41 days) and, thus, a longer AE reporting period. To normalize the incidence of AEs to the reporting period, the rate of AEs (reported from the first dose date through 30 days after the end date of the treatment phase) per patient-year was calculated. The median (range) rate of AEs per patient-year was 75.68 (10.4-243.5) in the CPX-351 arm and 87.22 (11.1-248.4) in the 7+3 arm. The median (range) rate of AEs per patient-year among patients who achieved a CR+CRi was 62.97 (18.3-175.7) in the CPX-351 arm and 74.38 (29.2-159.1) in the 7+3 arm. The median (range) rate of grade ≥3 AEs per patient-year was 12.24 (0.0-79.7) with CPX-351 and 13.53 (0.0-116.9) with 7+3. In contrast to the overall rate of AEs, the median (range) rate of serious AEs per patient-year was higher in the CPX-351 arm (3.15 [0.0-36.5]) than in the 7+3 arm (0.0 [0.0-31.0]). This may be due, in part, to a greater proportion of patients in the CPX-351 arm receiving consolidation therapy in an outpatient setting (51% of patients in cycle 1 and 61% in cycle 2) compared with the 7+3 arm (6% and 0% of patients in cycles 1 and 2, respectively) as, for these patients, management of AEs may have required a move to a hospital setting, which is one of the criteria for classifying an AE as a serious AE. The most frequently reported serious AEs were febrile neutropenia (CPX-351, 8%; 7+3, 5%), respiratory failure (7%; 5%), ejection fraction decreased (6%; 6%), sepsis (8%; 3%), and pneumonia (7%; 4%). Early mortality rates were lower for patients receiving CPX-351 versus 7+3 at both 30 days (5.9% vs 10.6%, respectively) and 60 days (13.8% vs 21.2%).

Although the proportions of patients who experienced individual AEs was similar between treatment arms, the median length of the treatment phase was approximately 50% longer for the CPX-351 arm than for the 7+3 arm, leading to evaluation of the rate of AEs per patient year. In this analysis, the rates of AEs per patient-year and early mortality were lower with CPX-351 than with conventional 7+3.