Based on findings that showed the addition of the BCL-2 inhibitor venetoclax to hypomethylating agents (HMAs) improved overall response rates (ORRs) and overall survival (OS) compared with HMAs alone, a study was designed to investigate the safety and efficacy of venetoclax combined with CPX-351, a fixed-dose liposomal formulation of daunorubicin and cytarabine, in patients with acute myeloid leukemia (AML).
The dose of CPX-351 was constant and consisted of daunorubicin 44 mg/m2 plus cytarabine 100 mg/m2 intravenously on days 1, 3, and 5 during induction and daunorubicin 29 mg/m2 plus cytarabine 65 mg/m2 intravenously on days 1 and 3 during consolidation. The safety lead-in cohort consisted of patients with relapsed or refractory (R/R) AML treated with a starting effective dose of venetoclax of 300 mg (at dose level 1) on days 2 to 21. After day 14, interruption of venetoclax was allowed if the day 14 bone marrow was hypocellular and without evidence of leukemia. Venetoclax dose adjustments were made for concomitant moderate and strong CYP3A inhibitors. Dose level 2 was explored (venetoclax 300 mg on days 2-8) and expanded after 3 of 6 patients experienced dose-limiting toxicity (DLT; cytopenias >43 days). After safety was established, 2 expansion cohorts were opened to confirm safety and efficacy. Cohort A included patients with R/R AML and cohort B included patients with newly diagnosed AML. Patients with adequate organ function (Eastern Cooperative Oncology Group performance status <2) were allowed on study as well as patients with prior venetoclax exposure.
At the time of data cutoff, 18 patients had been treated on study, which included 12 (67%) in the lead-in cohort, 5 (28%) in cohort A, and 1 (6%) in cohort B. The median age was 51 years (range, 29-71 years). Seventeen (94%) of the 18 patients had R/R AML with a median of 2 (range, 1-8) prior therapies. One (6%) patient had newly diagnosed treated-secondary AML. A total of 9 (50%) patients had adverse karyotype; 6 (33%) had complex karyotype and 6 (33%) had TP53 mutations. Seven (41%) patients with R/R AML had received prior venetoclax. A single patient with newly diagnosed AML (who had prior HMA plus venetoclax and allogeneic stem-cell transplant [allo-SCT] for myelodysplastic syndrome) achieved minimal residual disease–negative complete response (CR).
Of 16 evaluable patients with R/R AML, there was 1 (6%) CR, 6 (33%) CR with incomplete hematologic recovery, and 1 (6%) morphologic leukemia-free state resulting in an ORR of 44%. In patients without prior venetoclax exposure, the ORR was 60% (6/10) compared with just 17% (1/6 evaluable) among those with prior venetoclax exposure. Of the responding patients, 86% (6/7) went on to allo-SCT. The median OS overall was 6.4 months, and the landmark 6-month OS rate was 53%. Among responders, the median OS and relapse-free survival were not reached, with 6-month OS and relapse-free survival rates of 86%. The 4-week mortality rate was 11%, and the 8-week mortality rate was 22%. The starting dose level 1 was above the maximum tolerated dose of the combination (DLTs included prolonged neutropenia and thrombocytopenia). The most frequent grade 3/4 serious adverse events were infection, nausea, pneumonia, and myelosuppression.
In conclusion, CPX-351 plus 7 days of venetoclax was tolerable, with acceptable toxicities, among patients with R/R AML. In this high-risk cohort, CPX plus venetoclax demonstrated encouraging activity, particularly for patients without prior venetoclax exposure. Nearly all responders moved on to allo-SCT. Study enrollment continues.
Kadia TM, Borthakur G, Takahashi K, et al. Phase II Study of CPX-351 plus Venetoclax in Patients with Acute Myeloid Leukemia (AML). Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 28.