Roxanne Nelson, BSN, RN

June 27, 2016

A new liposomal formulation of chemotherapy agents has produced such promising results in a phase 3 clinical trial that experts say it should become a standard of care in the treatment of acute myeloid leukemia (AML), even though it is not yet approved.

The product, CPX-351 (Vyxeos, Celator Pharmaceuticals, Inc) is a liposomal formulation containing a fixed combination of cytarabine and daunorubicin in a 5:1 molar ratio that maximizes synergy, according to the manufacturer. The liposomal formulation results in preferential uptake of the drug into leukemic cells, the company says. It intends to submit the results of the phase 3 study to regulators later this year.

The results, presented at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting, show that frontline treatment with CPX-351 significantly improved overall survival, event-free survival, and response rates in comparison with the standard regimen of cytarabine and daunorubicin (7+3) among older patients with high-risk or secondary AML.

"Based on these data, CPX-351 should be considered as the new standard for first-line treatment of older patients with high-risk or secondary AML who are fit for intensive chemotherapy," said Joseph G. Jurcic, MD, professor of medicine at Columbia University Medical Center, in New York City. He was reviewing the new findings at a "highlights of the day" session on hematologic malignancies.

Overall, AML is a "daunting disease" to treat, he noted, especially for older patients.

AML is a daunting disease to treat. Dr Joseph Jurcic

Survival for AML patients younger than 55 years is about 40% to 50%. Although there has been some improvement in survival during the past few decades, for older patients, there really has been no improvement at all; the median survival is typically in the range of 6 months for such patients, Dr Jurcic commented.

"So clearly, new agents are needed for this very difficult population," he said.

A few studies with new agents, in addition to CPX-351, were presented at the meeting, leading him to comment: "I believe that the drought of new drugs for AML is about to end."

CPX-351 Superior for All Endpoints

Results from the phase 3 study were presented at the meeting by Jeffrey E. Lancet, MD, senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center, Tampa, Florida.

The study was conducted in 309 AML patients aged 60 to 75 years. Dr Lancet noted that they were all considered to be at high risk, meaning that they had therapy-related AML, or that they had a history of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (with or without prior hypomethylator treatment), or that they had AML with MDS-related cytogenetic abnormalities.

He pointed out that patients with secondary AML have emerged as an important subgroup with a very poor prognosis. These patients account for a quarter of all AML patients, and they do "considerably worse than de novo patients."

In the study, patients were randomly assigned to received either CPX-351 (100 units/m2, days 1, 3, 5) or the standard 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy.

The results showed a significant improvement in overall survival in the CPX-351 arm compared with the 7+3 arm ( 9.56 months vs 5.95 months; hazard ratio (HR), 0.69; P = .005).

There was also a significant improvement in event-free survival (2.53 months vs 1.31 months; HR = 0.74; P = .021), although this improvement was not as robust as the improvement in overall survival, Dr Lancet commented.

The complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi) rates were 47.7% for CPX-351 vs 33.3% for 7+3, showing a relative benefit of 43.2% with CPX-351 (P = .016).

For CR alone, the rates were 37.3% and 25.6% in favor of CPX-351 (P = .04).

"As a primary measurement of toxicity and safety, we measured the early mortality rate," said Dr Lancet. "There appeared to be a modest decrease in early mortality at both 30 days and 60 days favoring CPX compared to 7+3."

Importantly, the deaths attributable to aggressive AML were lower in the CPX-351 arm. "This may explain why the 60-day death rate may have been lower overall in the CPX arm, as a function of improved efficacy rather than an improved safety signal," he emphasized.

Rates of grade 3-5 adverse events were equal (92% vs 91%) in both groups. Such events were similar with respect to frequency and severity, and similar numbers of patients underwent transplant in both arms.

"The safety of CPX-351 was comparable to 7+3, and outcomes following transplant ― although the numbers are small — appear to favor CPX-351," Dr Lancet said.

The study was supported by Celator. Dr Juracic has relationships with Alexion, Sunesis, Amgen, Bayer, and Seattle Genetics and has received institutional research funding from Actinium, Celgene, TetraLogic, Ambit Biossciences, and Astellas. Dr Lancet has relationships with Amgen, Asterias Biotherapeutics, Baxalta, Boehringer, Ingelheim, Celgene, Karyopharm Tehrapeutics, and Novartis and has received institutional research funding from Celgene and Pfizer.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract 7000. Presented June 4, 2016.


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