Phase Ib/II Study of CPX-351 in Combination with Venetoclax in Patients with Newly Diagnosed, High Risk Acute Myeloid Leukemia

Background CPX-351 is a nanoscale liposome of a fixed 5:1 molar ratio of cytarabine and daunorubicin which has improved survival in pts with secondary acute myeloid leukemia (AML). Venetoclax (ven) is a BCL2 inhibitor which, in combination with azacitidine or cytarabine, has become the standard of care for older pts with AML. Ven has demonstrated synergy with intensive chemotherapy, with high complete remission rates in newly diagnosed (ND) and relapsed/refractory (RR) AML. In this study, we aim to assess the efficacy and safety of CPX-351 plus ven (CPX-ven) in ND AML. Methods This is a phase Ib/II study to assess the combination of CPX-351 and Venetoclax in newly diagnosed AML patients. Pts aged 18 - 69 with ND AML with adequate liver, renal, and cardiac function, and ECOG performance status ≤2 were enrolled. Patients who had received hypomethylating agents (HMAs) for a prior MDS or CMML (treated secondary AML , tsAML) were eligible. A phase Ib safety lead-in and dose finding cohort determined the recommended phase 2 dose: CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 IV on D1, 3 and 5 of induction, and daunorubicin 22 mg/m2 IV on D1 and 3 during consolidation). Ven was given on D2-8 of each cycle at a dose of 300mg daily and modified appropriately for concomitant CYP3A inhibitors. The primary outcome measure was complete remission (CR) or CR with incomplete count recovery (CRi). Overall survival (OS), Relapse-free survival (RFS) and Event-free survival (EFS) were analyzed by using Kaplan-Meier method. Results Eighteen patients have been treated. 11 (61%) are male. Median age was 59 yrs (range, 43-69). 12 pts (67%) had prior myeloid malignancies (3 (17%) CMML and 9 (50%) MDS). 5 (28%) pts had a previous non-myeloid malignancy. Adverse risk karyotype was present in 13 (72%) pts. Specifically, karyotype was Diploid in 4 (22%) pts, -7/7q- in 4 (22%) pts, and complex in 8 (46%) pts. Mutations in TP53 were present in 5 (28%) pts, ASXL1 in 4 (22%), NRAS in 4 (22%), and IDH2 in 2 (11%) pts. Among the patients with prior myeloid malignancies, 9 (75%) had received treatment with HMAs prior to their diagnosis of AML (ts-AML). Median number of cycles received were 2 (1-5). Overall response rate (ORR) was 78% (14/18) including 5 CR (28%), 8 CRi (44%), and 1 MLFS (6%). Of the responding patients, 5 (38%) achieved undetectable measurable residual disease (MRD) by flow cytometry. Among the responding pts, 12 (67%) underwent stem cell transplantation (SCT). With a median follow up of 11.5 months, the OS, RFS, and EFS were 12.9, 26.5, and 8.7 months, respectively. The most common serious adverse events reported were: neutropenic fever in 3 (17%) pts, and hemorrhage in 1 (6%) pt. The 4- and 8-week mortality rates were 0% and 11%, respectively. Of the 9 pts who had ts-AML, 5 (55%) proceeded to SCT, 2 pts died during treatment, and 1 pt did not respond. Conclusions: The combination of CPX-351 and 7 days of Venetoclax is a tolerable and effective regimen for patients with newly diagnosed high-risk AML, including those with tsAML. The regimen produced a high ORR and allowed most patients to proceed to SCT. Further prospective controlled trials to evaluate this combination are warranted.