Exploratory Analysis of the Efficacy and Safety of CPX-351 Versus 7+3 By European Leukemianet (ELN) 2017 Risk Groups in a Phase 3 Study of Older Adults with High-Risk/Secondary Acute Myeloid Leukemia

Introduction: CPX-351 (Vyxeos^®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes. A phase 3 study (NCT01696084) in older patients aged 60 to 75 years with newly diagnosed high-risk/secondary AML demonstrated significantly longer overall survival (OS) with CPX-351 vs conventional 7+3, with a comparable safety profile. This exploratory post hoc analysis of the phase 3 study evaluated outcomes by AML risk subgroups according to the ELN 2017 criteria.

Methods: Inclusion criteria did not consider risk classification. Patients were randomized 1:1 to receive 1 to 2 induction cycles of CPX-351 (100 units/m² [cytarabine 100 mg/m² + daunorubicin 44 mg/m²] as a 90-minute infusion on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m²/day continuously for 7 days + daunorubicin 60 mg/m² on Days 1, 2, and 3 [2nd induction: 5+2]). Patients achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Patients could receive a hematopoietic cell transplant (HCT) at the physician’s discretion. In this subgroup analysis, patients from the phase 3 study were classified retrospectively into risk subgroups per the ELN 2017 criteria: favorable-risk AML, intermediate-risk AML, or adverse-risk AML.

Results: Of 309 patients enrolled in the study, 149/153 in the CPX-351 arm and 148/156 in the 7+3 arm had molecular data available for ELN 2017 risk classification and were included in this analysis. In the CPX-351 and 7+3 arms, respectively, 10 (7%) and 7 (5%) had favorable-risk AML, 40 (27%) and 41 (28%) had intermediate-risk AML, and 99 (66%) and 100 (68%) had adverse-risk AML by ELN. Due to small patient numbers, outcomes for the subgroup of patients with favorable-risk AML were not evaluated.

In patients with intermediate-risk AML, CR+CRi was achieved by 23 (58%) patients with CPX-351 vs 16 (39%) patients with 7+3; in those with adverse-risk AML, CR+CRi was achieved by 41 (41%) vs 26 (26%). Median OS was longer with CPX-351 vs 7+3 in patients with intermediate-risk AML (11.9 vs 7.8 months; HR = 0.68 [95% CI: 0.41, 1.16]; Figure 1A) and adverse-risk AML (7.7 vs 5.5 months; HR = 0.63 [95% CI: 0.46, 0.86]; Figure 1B). In patients with TP53 mutations in the adverse-risk group, median OS was 5.7 months with CPX-351 (n = 24/99) vs 5.1 months with 7+3 (n = 31/100; HR = 1.00 [95% CI: 0.57, 1.75]); in patients without TP53 mutations in the adverse-risk group, median OS was 9.6 vs 5.6 months (HR = 0.55 [95% CI: 0.38, 0.81]).

In patients with intermediate-risk AML, HCT was received by 14 (35%) in the CPX-351 arm vs 14 (34%) in the 7+3 arm; median OS landmarked from the HCT date was not reached with CPX-351 vs 13.0 months with 7+3 (HR = 0.46 [95% CI: 0.16, 1.39]). In patients with adverse-risk AML, HCT was received by 32 (32%) patients in the CPX-351 arm vs 24 (24%) patients in the 7+3 arm; median OS landmarked from the HCT date was not reached with CPX-351 vs 7.1 months with 7+3 (HR = 0.44 [95% CI: 0.21, 0.93]). In patients with TP53 mutations in the adverse-risk group who underwent HCT, median OS landmarked from the HCT date was 10.0 months (n = 4) vs 6.4 months with 7+3 (n = 10); in patients without TP53 mutations in the adverse-risk group who underwent HCT, median OS landmarked from the HCT date was not reached with CPX-351 (n = 28) vs 11.2 months with 7+3 (n = 14).

Early mortality rates by Day 60 were 13% vs 20% with CPX-351 vs 7+3, respectively, in patients with intermediate-risk AML and 15% vs 25% in patients with adverse-risk AML. Adverse events in ≥50% of patients with intermediate-risk AML were febrile neutropenia (CPX-351: 85%; 7+3: 70%), nausea (48%; 63%), diarrhea (45%; 68%), peripheral edema (45%; 53%), and constipation (33%; 50%), and in patients with adverse-risk AML were febrile neutropenia (63%; 70%), nausea (47%; 51%), and diarrhea (44%; 66%).

Conclusions: In this post hoc analysis, CPX-351 improved median OS, remission rates, and post-HCT outcomes vs 7+3 in patients with intermediate- or adverse-risk AML per the ELN 2017 criteria, with a safety profile consistent with the overall study population and the known safety profile of 7+3. Abstract previously published by EHA in HemaSphere, 2020;4:S1.