Credit: Rhoda Baer
A drug that combines 2 chemotherapy agents into 1 can be more effective than treatment with the individual agents in combination, results of a phase 2 study suggest.
The drug, CPX-351, is a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.
In older patients with acute myeloid leukemia (AML), CPX-351 elicited a higher response rate than combination treatment with cytarabine and daunorubicin, although the difference was not significant.
Likewise, there were no significant differences in event-free survival (EFS) or overall survival (OS) between the 2 treatment groups.
However, CPX-351 conferred a significant response benefit among patients with poor cytogenetics and a significant survival benefit in patients with secondary AML (sAML).
Jeffrey Lancet, MD, of the Moffitt Cancer Center in Tampa, Florida, and his colleagues reported these results in Blood. The study was funded by Celator Pharmaceuticals, the company developing CPX-351.
Treatment details
The researchers analyzed 126 newly diagnosed AML patients who were 60 to 75 years of age.
Patients were randomized to receive CPX-351 (n=85) or “control” treatment consisting of cytarabine and daunorubicin (n=41). The 2 treatment groups were well-balanced for disease and patient characteristics at baseline.
As induction, patients in the CPX-351 arm received a 90-minute infusion of the drug at 100 units/m2 on days 1, 3, and 5 (delivering 100 mg/m2 cytarabine and 44 mg/m2 daunorubicin with each dose). Second induction and consolidation courses were given at 100 units/m2 on days 1 and 3.
Patients in the control arm received induction therapy consisting of cytarabine at 100 mg/m2/day by 7-day continuous infusion and daunorubicin at 60 mg/m2/day on days 1, 2, and 3. Daunorubicin could be reduced to 45 mg/m2/day at the investigator’s discretion for patients with advanced age, poor performance status, or reduced liver/kidney function.
The choice of consolidation therapy was at the investigator’s discretion as well. The recommended regimens included cytarabine at 100 to 200 mg/m2 for 5 to 7 days, with or without daunorubicin or intermediate-dose cytarabine (1.0 to 1.5 g/m2/dose).
Response and survival
The response rate was higher in the CPX-351 arm than in the control arm—66.7% and 51.2%, respectively (P=0.07), which met the predefined criterion for success (P<0.1). Response was defined as a complete response (CR) or a complete response with incomplete blood count recovery (CRi).
CRs occurred in 48.8% of patients in both arms. But CRis favored the CPX-351 arm over the control arm—17.9% and 2.4%, respectively.
Likewise, response rates favoring CPX-351 occurred in patients with adverse cytogenetics and sAML.
Among patients with adverse cytogenetics, the response rate was 77.3% in the CPX-351 arm and 38.5% in the control arm (P=0.03). And among patients with sAML, the response rate was 57.6% in the CPX-351 arm and 31.6% in the control arm (P=0.06).
The median OS was 14.7 months in the CPX-351 arm and 12.9 months in the control arm. The median EFS was 6.5 months and 2.0 months, respectively. These differences were not statistically significant.
However, sAML patients treated with CPX-351 had significantly better OS than sAML patients in the control arm. The median OS was 12.1 months and 6.1 months, respectively (P=0.01). And the median EFS was 4.5 months and 1.3 months, respectively (P=0.08).
Safety results
By day 60, 4.7% of patients in the CPX-351 arm and 14.6% of patients in the control arm had died. All of these deaths occurred in high-risk patients, particularly those with sAML.
Two patients died of intracranial hemorrhage during CPX-351 consolidation. One of these deaths was associated with head trauma and relapsed AML, and the other was from chemotherapy-induced thrombocytopenia.
For many of the most common adverse events, there were minimal differences between the treatment arms. These events included febrile neutropenia, infection, rash, diarrhea, nausea, edema, and constipation.
Patients in the CPX-351 arm had a higher incidence of grade 3-4 infection than controls—70.6% and 43.9%, respectively—but not infection-related deaths—3.5% and 7.3%, respectively.
The median time to neutrophil recovery (to ≥ 1000/μL) was longer in the CPX-351 arm than the control arm—36 days and 32 days, respectively. The same was true for platelet recovery (to ≥ 100,000/μL)—37 days and 28 days, respectively.
Researchers are now conducting a phase 3 trial of CPX-351, which is open and recruiting patients.
