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 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. In a randomized, phase 3 study (NCT01696084) of CPX-351 versus conventional cytarabine/daunorubicin (7+3 regimen) in adults aged 60-75 years with newly diagnosed, secondary AML (ie, therapy-related AML or AML with myelodysplasia-related changes), CPX-351 significantly improved overall survival (OS) and remission rates (Lancet JE, et al. ASCO 2016. Abstr 7000). Oligoblastic sAML, often defined as bone marrow blasts 20%-29%, shares many biologic and clinical features with myelodysplastic syndromes (MDS) and was designated RAEB-t by the French-American-British classification. The optimal treatment paradigm for these patients is unclear. A subgroup analysis of the phase 3 study was conducted to determine the efficacy and safety of CPX-351 in patients with these MDS characteristics.

Eligible patients were 60-75 years of age and had untreated, secondary or high-risk AML, including therapy-related AML, AML with antecedent MDS or chronic myelomonocytic leukemia, or de novo AML with a MDS karyotype. Patients were randomized 1:1 to receive 1-2 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/m2 on Days 1-3 [Days 1-2 for second induction]). For patients with complete response (CR) or CR with incomplete platelet or neutrophil recovery (CRi), up to 2 cycles of consolidation could be given (CPX-351 65 units/m2 [65 mg/m2 cytarabine + 29 mg/m2 daunorubicin] on Days 1 and 3 or cytarabine 100 mg/m2/day for 5 days + daunorubicin 60 mg/m2 on Days 1-2).

The study enrolled 309 patients, 77 of which met the criteria for RAEB-t AML (CPX-351, n = 42; 7+3, n = 35). Patient demographics were generally well balanced between treatment groups (Table).

The median OS of all patients with RAEB-t AML was 9.17 months (95% confidence interval [CI]: 5.95, 12.19). Patients in the CPX-351 arm had significantly prolonged median OS (12.50 months [95% CI: 7.75, not estimable]) compared with those in the 7+3 arm (5.95 months [95% CI: 4.27, 9.46]; HR = 0.54 [95% CI: 0.32, 0.94]; Figure). The Kaplan-Meier-estimated 2-year OS rates were 37% and 14% for patients receiving CPX-351 and 7+3, respectively. In a subanalysis that excluded patients treated previously with hypomethylating agents (CPX-351, n = 16; 7+3, n = 14 excluded), median OS among patients with RAEB-t AML was 19.15 months (95% CI: 9.17, not estimable) in the CPX-351 arm and 5.68 months (95% CI: 2.33, 9.95) in the 7+3 arm (HR = 0.46 [95% CI: 0.22, 0.97]). The rate of CR+CRi was 47.6% (including 35.7% with a CR) in the CPX-351 arm versus 42.9% (including 31.4% with a CR) in the 7+3 arm among patients with RAEB-t AML.

The incidence of treatment-emergent adverse events (TEAEs) in patients with RAEB-t AML was generally comparable between treatment arms and consistent with previous reports from the overall study population. The most frequently reported (≥50%) TEAEs in this subpopulation were febrile neutropenia (CPX-351, 67% and 7+3, 82%), nausea (60% and 58%), diarrhea (43% and 70%), and peripheral edema (36% and 61%). Serious AEs were reported in 43% and 33% of patients with RAEB-t AML in the CPX-351 and 7+3 arms, respectively; serious TEAEs occurring in ≥5% of patients included febrile neutropenia (CPX-351, 7% and 7+3, 3%), disease progression (2% and 6%), and ejection fraction decreased (2% and 6%). No patient with RAEB-t AML discontinued treatment due to a TEAE. Other than disease progression (CPX-351, n = 1 and 7+3, n = 2), no more than 1 patient in this subanalysis experienced any specific grade 5 TEAE. Among patients with RAEB-t AML, early mortality rates were 10% and 9% at Day 30 in the CPX-351 and 7+3 arms, respectively, and 17% and 18% at Day 60.

Survival was superior with CPX-351 compared with 7+3 in patients with RAEB-t AML and high-risk disease features, and safety profiles were comparable between the treatment arms. These results suggest that CPX-351 should be explored further in related disease groups, including higher-risk MDS.


Lin: Jazz Pharmaceuticals: Consultancy. Uy: Boehringer Ingelheim: Consultancy; Novartis: Consultancy, Other: Travel Suppport; GlycoMimetics: Consultancy. Wieduwilt: Reata Pharmaceuticals: Equity Ownership; Sigma-Tau: Research Funding. Stuart: Amgen: Consultancy, Honoraria; Incyte: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Astellas: Research Funding; Cantex: Research Funding; MedImmune: Research Funding; Bayer: Research Funding; Celator/Jazz: Research Funding. Schiller: Celator/Jazz: Research Funding. Rubenstein: Cyclacel, Astex, Novartis, and EMD Serrano: Other: Travel compensation to investigator meetings; Alexion: Consultancy, Honoraria, Speakers Bureau. Stock: Amgen: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Foster: Celator: Research Funding; Shire: Honoraria; Incyte: Honoraria; Pfizer: Research Funding; Amgen: Honoraria; Celgene: Research Funding; Macrogenics: Research Funding. Podoltsev: Ariad: Consultancy; CTI biopharma/Baxalta: Consultancy; Incyte: Consultancy; Alexion: Consultancy. An: Celator/Jazz: Employment, Equity Ownership. Faderl: Celator/Jazz: Employment, Equity Ownership. Louie: Celator/Jazz Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Lancet: Pfizer: Other: Institutional research funding; Biopath, Biosight, Boehringer Ingelheim, Celator/Jazz, Celgene, Janssen, Karyopharm Therapeutics, and Novartis: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.