CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia

Abstract

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Trial registration: ClinicalTrials.gov NCT01696084.

Fig 1.

CONSORT diagram. (*) Patients without confirmation of therapy-related acute myeloid leukemia (AML), antecedent myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), or de novo AML with MDS-related cytogenetic abnormalities (n = 43; many of these screen failures were in patients with de novo AML without MDS-related cytogenetic abnormalities because results of the required bone marrow biopsy specimens were not available at the patients’ initial diagnosis); without pathologic diagnosis of AML according to WHO criteria with ≥ 20% blasts in the peripheral blood or bone marrow (n = 30); with a history of myeloproliferative neoplasms, except CMML (n = 6); or with acute promyelocytic leukemia (t[15;17]) or favorable cytogenetics (t[8;21] or inv16 if known at the time of random assignment; n = 3). (†) Patients without serum creatinine < 2.0 mg/dL, serum total bilirubin < 2.0 mg/dL, and serum ALT or AST less than three times the upper limit of normal. (‡) Other includes patients with myocardial impairment of any cause that resulted in heart failure by New York Heart Association criteria (n = 3); active (uncontrolled, metastatic) second malignancies (n = 1); active fungal infection, hepatitis B or C, or HIV (n = 1); cardiac ejection fraction < 50% (n = 1); incorrect age (n = 1); secondary malignancy in remission (n = 1); and unspecified (n = 24). 7+3, standard-of-care cytarabine plus daunorubicin chemotherapy; CPX-351, dual-drug liposomal encapsulation of cytarabine and daunorubicin.

Fig 2.

Median overall survival (OS) and event-free survival (EFS). Kaplan-Meier estimates of (A) OS and (B) EFS are shown for the overall intention-to-treat population, and Kaplan-Meier estimates of (C) OS landmarked from the date of transplantation are shown for patients in the intention-to-treat population who received a hematopoietic cell transplant. EFS was defined as the time from random assignment to the date of induction treatment failure, relapse from complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi), or death as a result of any cause, whichever came first. Patients alive and not known to have any of these events were censored on the latter of their last dates of disease assessment or hematology assessment. For patients who achieved CR or CRi, duration of remission was measured from the date of remission (CR or CRi) until the date of relapse or death as a result of any cause. Patients not known to have relapsed or died at the last follow-up were censored in a similar fashion as described for EFS. 7+3, standard-of-care cytarabine plus daunorubicin chemotherapy; CPX-351, dual-drug liposomal encapsulation of cytarabine and daunorubicin; HR, hazard ratio.

Fig 3.

Kaplan-Meier estimates of overall survival by (A) age subgroup and (B) baseline patient characteristics. (*) Includes patients in the prespecified randomization strata of antecedent myelodysplastic syndrome (MDS) with prior hypomethylating agent (HMA) exposure as well as patients in other strata (eg, therapy-related acute myeloid leukemia [AML], antecedent chronic myelomonocytic leukemia [CMML]) who had previously received HMAs. Some patients received HMAs for therapy-related MDS, which then progressed to AML, and these patients may have been classified as having either therapy-related AML or antecedent MDS with prior HMA exposure. 7+3, standard-of-care cytarabine plus daunorubicin chemotherapy; CPX-351, dual-drug liposomal encapsulation of cytarabine and daunorubicin; FLT3, FMS-like tyrosine kinase 3; HR, hazard ratio; OS, overall survival.

Fig 4.

Most frequently reported adverse events. The percentage of patients with grade 1 and 2 and grade 3 to 5 events are shown for all adverse events that occurred in > 5% of patients in either treatment group as grade 3 to 5 events. 7+3, standard-of-care cytarabine plus daunorubicin chemotherapy; CPX-351, dual-drug liposomal encapsulation of cytarabine and daunorubicin.