ORLANDO – A novel liposomal combination of cytarabine plus daunorubicin produced higher complete remission rates than did the standard "7+3" cytarabine-daunorubicin induction regimen in older patients with untreated acute myeloid leukemia, reported investigators at the annual meeting of the American Society of Hematology.

In a phase IIB randomized trial, 66.7% of patients with newly diagnosed AML who underwent induction with the liposomal formulation, dubbed CPX-351, had complete remissions (CR) or complete remissions with incomplete peripheral blood count recovery (CRi), compared with 51.2% of patients who received induction with the 7+3 regimen, a difference that fell a bit shy of statistical significance (P = .0712), reported Dr. Jeffrey E. Lancet from the H. Lee Moffitt Cancer Center in Tampa.

CPX-351 was associated with significantly better overall survival in the subgroup of patients with secondary AML (median, 12.1 months vs. 6.1 months; log rank P = .01). The liposomal compound also appeared to have an edge in high cytogenetic risk patients, with 17 of 23 patients (73.9%) who received it having a remission, compared with 5 of 13 (38.5%) who were given the standard therapy, but this difference too fell just outside the boundary of significance (P = .07), said Dr. Lancet.

"In terms of future directions, we feel that there is a strong signal of activity with the drug, and phase III trials are being planned for sometime next year," he said. "There are still some options on the table to consider, including isolating the patient population to a secondary AML subgroup, to look at a more generalized group of high-risk AML patients, or perhaps to look at a more unselected group of patients, but I think that additional follow-up data and analysis will be necessary before making this decision."

CPX-351 is a liposome that delivers cytarabine and daunorubicin in a 5:1 molar ratio for more than 24 hours after infusion. The agent accumulates and persists in the bone marrow, and has been shown to have preferential uptake and intracellular release within leukemic blasts, compared with nonleukemic progenitor cells.

In phase I trials, CPX-351 was associated with clinical responses in patients with advanced AML, including some for whom 7+3 therapy had failed. Dose-limiting toxicities were hypertensive crisis, cardiomyopathies, and one case of prolonged cytopenia.

In the phase IIB trial, patients aged 60-75 years with newly diagnosed AML were randomly assigned in a 2:1 ratio to receive CPX-351 in doses of 100 U/m2 on days 1, 3 and 5, or 7+3 therapy with cytarabine 100 mg/m2 in a 7-day continuous infusion plus daunorubicin 60 mg/m2 on days 1, 2, and 3 – each regimen for one or two induction cycles. Patients who experienced CR or CRi then went on to one or two consolidation cycles. The trial included an optional crossover arm for patients in the 7+3 arm who had persistent AML following induction. The primary end point was the combined CR-plus-CRi rate.

In all, 126 patients from 18 sites in the United States and Canada were enrolled, 85 in the CPX-351 arm, and 41 in 7+3 arm. One patient who was initially enrolled in the CPX-351 arm was found to have Philadelphia chromosome–positive AML and was removed from the study for treatment with imatinib (Gleevec), leaving 84 patients on CPX-351 for the efficacy and safety analysis.

Following induction, 41 patients on CPX-351 (48.8%) had a CR, and 15 (17.9%) had a CRi, compared with 20 (48.8%) and 1 (2.4%) patients on the 7+3 regimen. An analysis of efficacy by subgroups showed that CPX-351 induced higher remission rates in patients younger than 70 years and those aged 70 and older, and in patients with secondary AML, compared with de novo disease, although the sample sizes for these comparisons were not sufficiently large to determine significance.

Early deaths from all causes were similarly lower in the CPX group at 30 days (3.5% vs. 7.3% for the 7+3 group) and at 60 days (4.7% vs. 14.6%; P = .053). All early deaths occurred in high-risk patients.

In the overall efficacy analysis, there were no significant differences between CPX-351 and 7+3 in either event-free survival (remission duration, 8.9 and 8.6 months, respectively) or overall survival (median, 14.7 and 12.9 months).

The optional crossover arm included 10 patients, 1 of whom switched after two induction cycles and 9 after one cycle. Of these patients, four had responses, and all four were alive at the 1-year follow-up.

The safety analysis showed that CPX-351 was associated with a higher percentage of grade 3 or 4 febrile neutropenia (63.5% vs. 51.2%) and clinical infections (70.6% vs. 46.3%), as well as with longer myelosuppression, including about 7 days longer neutrophil recovery, and about 10 days longer platelet recovery than was the case for patients receiving the standard chemotherapy. The higher incidence of infections with the experimental agent did not appear to result in worse outcomes, however, as the overall rate of deaths attributable to infections was low in each arm, Dr. Lancet said.

CPX-351 has orphan drug status for the treatment of AML, according to the Celator Web site.

Celator Pharmaceuticals sponsored the trial. Dr. Lancet disclosed that his center received compensation from the company, and he has served on the board of directors or advisory committees. Two coauthors also disclosed serving on the board or as advisors, and one is employed by the company.

Liposomal Cytarabine-Daunorubicin Improves AML Remission Rates