Older adult patients with newly diagnosed high-risk or secondary acute myeloid leukemia experienced a durable survival benefit when treated with CPX-351 over 7+3 cytarabine and daunorubicin chemotherapy.
The overall survival (OS) benefit of CPX-351 (Vyxeos) appears to more durable and robust than a regimen of conventional cytarabine for 7 days and daunorubicin for 3 days (7+3) for older patients with newly diagnosed high-risk or secondary acute myeloid leukemia (AML), according the final 5-year results of a phase 3 trial (NCT01696084) that was published in Lancet Haematology.
At a median follow-up of 60.91 months (IQR, 60.06-62.98) for patients in the CPX351 group and 59.93 months (IQR, 59.73-60.50) for patients in the 7+3 group, the median OS difference remained superior for patients who received CPX351. Investigators reported an OS of 9.33 months (95% CI, 6.37-11.86) for those in the experimental cohort compared with 5.95 months (95% CI, 4.99-7.75) for patients in the 7+3 group (HR = 0.70; 95% CI, 0.55-0.91).
“The results from this final 5-year follow-up analysis showed that CPX351 continued to provide overall survival and remission benefit versus 7+3 in patients with newly diagnosed high-risk or secondary acute myeloid [leukemia],” the investigators wrote. “Improved overall survival in patients [who were] given CPX351 was observed regardless of patient age and across most [AML] subtypes.”
A total of 309 patients with newly diagnosed high-risk or secondary AML were enrolled on the randomized trial between December 20, 2012, and November 11, 2014, and randomly assigned to receive either CPX-351 (n = 153) or the 7+3 regimen (n = 156).
Treatment consisted of up to 2 induction cycles of CPX-351, which was administered at a dose of 100 units/m2 intravenously on days 1, 3, and 5, as well as days 1 and 3 for the second induction. Those who received the standard chemotherapy regimen were treated with 100 mg/m2 per day of intravenous cytarabine for 7 days plus intravenous daunorubicin at 60 mg/m2 on days 1, 2, and 3 (7+3). For the second induction, cytarabine was given for 5 days and daunorubicin on days 1 and 2 (5+2).
The study enrolled older adult patients between the ages 60 to 75 years with a pathological diagnosis of AML according to World Health Organization 2008 criteria. Those with acute promyelocytic leukemia t(15;17) or other favorable cytogenetics known at the time of
random assignment, who received prior induction therapy for AML, or who had an active secondary malignancy or central nervous system involvement were not eligible to enroll. Additionally, an ECOG performance score of 0 to 2 was required.
Prior treatment with a hypomethylating agent (HMA) was similar across both study arms, including those in the prespecified randomized strata who had prior myelodysplastic syndrome, therapy-related AML, or chronic myelomonocytic leukemia and were exposed to an HMA.
The primary end point of the study was OS analyzed in all randomized patients.
Further OS estimates were found to be higher for patients in the CPX351 group compared with patients in the 7+3 group. For example, the 3-year OS estimates were 21% (95% CI, 15%-28%) for the CPX-351 group and 9% (95% CI, 5%-14%) for the 7+3 group. The 5-year OS estimates were 18% (95% CI, 12%-25%) and 8% (95% CI, 4%-13%) for the CPX351 and 7+3 groups, respectively.
Evaluations by post hoc subgroup analyses further validated superior OS data for patients in the CPX351 cohort vs the 7+3 cohort across most subgroups, although the research team notes some of the sample sizes in subgroup analyses were small.
In terms of safety, no additional adverse effect data were collected with the long-term follow-up outside of deaths. Progressive leukemia was the most common cause of death among patients in both groups, including 56% of those in the CPX-351 group and 53% in the 7+3 group. Additionally, 14% of deaths in both the CPX-351 (n = 17/124) and 7+3 cohorts (n = 19/140). Moreover, 5% of the deaths in each group were considered to be treatment related.
CPX351 is approved in the United States for the treatment of adult patients and children aged 1 year or older with newly diagnosed therapy-related AML or AML with myelodysplasiarelated changes, as well as in adults aged 18 years or older in the EU.
The approval was based on data from the primary end point analysis for this study after a median follow-up of 20.99 months. The median OS at this follow-up was 9.56 months (95% CI, 6.60-11.86) for the CPX-351 group compared with 5.95 months (95% CI, 4.99-7.75) for the 7+3 group (HR, 0.69; 95% CI, 0.52-0.90; P = .003).
“These results support the previous evidence that CPX351 has the ability to contribute to long-term remission and survival in patients aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid [leukemia], and further support the use of CPX351 in this patient population,” the study’s investigators concluded.
Lancet JE, Uy GL, Newell LF, et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021;8(7):e481-e491. doi:10.1016/S2352-3026(21)00134-4