Older patients (≥60 years of age) with acute myeloid leukemia (AML) often have lower remission rates and increased induction mortality with intensive induction chemotherapy, compared with younger patients. Previous small randomized studies of CPX-351 – a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio – suggested enhanced efficacy in this older patient cohort, compared with conventional induction, at least in patients with secondary AML.
Two presentations at the 2016 ASH Annual Meeting provided outcomes from a randomized, open-label, phase III study that included 309 patients (60-75 years of age) who were enrolled between December 2012 and November 2014 from 39 U.S. and Canadian sites. Newly diagnosed patients with secondary AML (defined in the protocol as a history or prior cytotoxic treatment, antecedent myelodysplastic syndromes [MDS], or AML with World Health Organization-defined MDS-related cytogenetic abnormalities) who received allogeneic hematopoietic cell transplantation (alloHCT) after induction therapy were included.
Patients were randomized 1:1 to receive:
- CPX-351 induction 100 units/m2 (cytarabine 100 mg/2 plus daunorubicin 44 mg/m2) on days 1, 3, and 5 (first induction only; n=153)
- Conventional 7+3 induction (cytarabine 100 mg/m2 per day for 7 days plus daunorubicin 60 mg/m2 on days 1-3 during first induction and cytarabine for 5 days plus daunorubicin 60 mg/m2 on days 1 and 2 for re-induction/first consolidation; n=156)
Ninety-one patients were eligible for and went on to receive alloHCT, including 52 (34%) from the CPX-351 cohort and 39 (25%) from the 7+3 cohort.
In the first presentation, Jeffrey E. Lancet, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and co-authors found that at 100 days post-transplant, mortality was 9.6 percent for those in the CPX-351 arm and 20.5 percent in the 7+3 arm, representing 53 percent fewer deaths in the CPX-351 cohort.1 Causes of death at <100 days post-transplant in the CPX-351 and 7+3 cohorts included refractory AML (3.8% and 7.7%, respectively); graft-versus-host disease (3.8% and 2.6%); renal, respiratory, multi-organ failure, or septic shock (0% and 2.6%); or unknown causes (1.9% and 0%).
“CPX-351 may provide an effective bridge to successful transplant for a very poor-risk subgroup of AML patients,” Dr. Lancet and co-authors concluded.
In the second presentation, Bruno C. Medeiros, MD, from the Department of Medicine/Hematology at Stanford University, and co-authors found that the complete response (CR) or CR with incomplete platelet or neutrophil recovery (CRi) rates for patients 60-69 years of age were 50 percent for those receiving CPX-351 and 36.3 percent for those receiving 7+3 (odds ratio [OR] = 1.76; 95% CI 1.00-3.10).2 For patients 70-75 years of age, the CR+CRi rate was 43.9 percent in the CPX-351 cohort and 27.8 percent in the 7+3 cohort (OR=2.03; 95% CI 0.92-4.49). See TABLE for overall survival (OS) rates.
The rate of patients receiving alloHCT in the 60-69 years of age cohort was 37.5 percent in the CPX-351 group and 32.4 percent in the 7+3 cohort (OR=1.25; 95% CI 0.70-2.25) and 28.1 percent and 11.1 percent, respectively, in the 70-75 years of age cohort (OR=3.12; 95% CI 1.12-8.72).
Grade 3-5 adverse events (AEs) occurred in 92 percent and 91 percent of patients receiving CPX-351 and 7+3, respectively. The most common grade 3-5 non-hematologic AEs were febrile neutropenia (68% and 71%), pneumonia (20% and 15%), and hypoxia (13% and 15%).
“CPX-351 treatment had substantially greater median OS and higher CR+CRi rates than standard 7+3 in both age groups,” Dr. Medeiros and co-authors concluded. “In addition, somewhat more patients in each age group in the CPX-351 arm received alloHCT … with the greatest difference in the older age group.”
The age subset study is limited by its small patient cohort.
- Lancet JE, Hoering A, Uy GL, et al. Survival following allogeneic hematopoietic cell transplantation in older high-risk acute myeloid leukemia patients initially treated with CPX-351 liposome injection versus standard cytarabine and daunorubicin: subgroup analysis of a large phase III trial. Abstract #906. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.
- Medeiros BC, Lancet JE, Cortes JE, et al. Analysis of efficacy by age for patients aged 60-75 with untreated secondary acute myeloid leukemia (AML) treated with CPX-351 liposome injection versus conventional cytarabine and daunorubicin in a phase III trial. Abstract #902. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.