Five-Year Final Results of a Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed High-Risk/Secondary Acute Myeloid Leukemia (AML): Outcomes By Age Subgroup and Among Responders

Introduction: CPX-351 (Vyxeos^®; daunorubicin and cytarabine liposome for injection) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio. In a pivotal, randomized phase 3 study (NCT01696084) in patients aged 60 to 75 y with newly diagnosed high-risk/secondary AML, after a median follow-up of 20.7 mo, induction followed by consolidation with CPX-351 significantly improved median overall survival (OS) versus conventional 7+3, with a comparable safety profile. This primary endpoint analysis of the study helped to support the approval of CPX-351 by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Here, we report the prospectively planned, final 5-y follow-up results from this phase 3 study, including outcomes by age subgroup.

Methods: 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-min infusion on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m²/d continuously for 7 d + daunorubicin 60 mg/m² on Days 1 to 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 hematopoietic cell transplantation (HCT) at the physician’s discretion. Patients were followed until death or up to 5 y after randomization. Subgroup analyses were conducted in patients who achieved CR or CRi and in those aged 60 to 69 y and 70 to 75 y.

Results: In total, 309 patients were randomized to CPX-351 (n = 153) or 7+3 (n = 156). The Kaplan-Meier–estimated survival rates were higher for CPX-351 versus 7+3 at 3 y (21% vs 9%) and 5 y (18% vs 8%). Among patients who died, the most common primary cause of death was progressive leukemia in both arms (CPX-351: 56%; 7+3: 53%). After a reverse Kaplan-Meier–estimated median follow-up of 60.65 mo (10th to 90th percentile: 58.22, 63.90), improved median OS with CPX-351 versus 7+3 was maintained (9.33 vs 5.95 mo; HR = 0.70 [95% CI: 0.55, 0.91]; Figure 1), with an HR that was very stable and consistent with the prior primary endpoint analysis (9.56 vs 5.95 mo; HR = 0.69 [95% CI: 0.52, 0.90]). Median OS for the CPX-351 arm differed from that reported for the primary endpoint analysis due to a patient death reported after the cutoff date for that analysis.

When analyzed by age subgroup, improved median OS with CPX-351 versus 7+3 was also maintained in patients aged 60 to 69 y (9.59 vs 6.87 mo; HR = 0.73 [95% CI: 0.54, 0.99]; Figure 2A) and in those aged 70 to 75 y (8.87 vs 5.62 mo; HR = 0.52 [95% CI: 0.34, 0.77]; Figure 2B).

HCT was received by 53 (35%) and 39 (25%) patients in the CPX-351 and 7+3 arms, respectively. Among patients who underwent HCT, the Kaplan-Meier–estimated survival rate landmarked from the date of HCT was higher for CPX-351 versus 7+3 at 3 y (56% vs 23%), and median OS landmarked from the date of HCT was not reached for CPX-351 versus 10.25 mo for 7+3 (HR = 0.51 [95% CI: 0.28, 0.90]; Figure 3).

CR or CRi was achieved by 73 (48%) and 52 (33%) patients in the CPX-351 and 7+3 arms, respectively. Among patients who achieved CR or CRi, the Kaplan-Meier–estimated survival rate was higher for CPX-351 versus 7+3 at 3 y (36% vs 23%) and at 5 y (30% vs 19%), and median OS was longer with CPX-351 versus 7+3 (21.72 vs 10.41 mo; HR = 0.59 [95% CI: 0.39, 0.88]). Additionally, 41/73 (56%) patients in the CPX-351 arm and 24/52 (46%) in the 7+3 arm who achieved CR or CRi proceeded to HCT; in these patients, median OS landmarked from the date of HCT was not reached for CPX-351 versus 11.65 mo for 7+3 (HR = 0.50 [95% CI: 0.26, 0.97]).

Conclusions: After 5 y of follow-up, improved OS with CPX-351 versus conventional 7+3 chemotherapy was maintained in this phase 3 study in the overall study population regardless of patient age, in those who underwent HCT, and among patients who achieved CR or CRi. The longer OS with CPX-351 versus 7+3 in patients who underwent HCT and in those who achieved CR or CRi suggests potentially deeper responses may be achieved with CPX-351. These data support prior evidence that CPX-351 has the ability to produce or contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML.

Abstract previously published by EHA in HemaSphere, 2020;4:S1 and by ASCO in J Clin Oncol, 2020;38(15 suppl).