P515: LOWER-INTENSITY CPX-351 + VENETOCLAX FOR PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA WHO ARE UNFIT FOR INTENSIVE CHEMOTHERAPY

Abstract

Background: CPX-351 (Europe: Vyxeos® liposomal; United States: Vyxeos®) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults in Europe and patients aged ≥1 year in the United States who are candidates for intensive chemotherapy (IC). However, the appropriate dosage of CPX-351 in patients unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit patients with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN clinically. Aims: Our study evaluates the safety and efficacy of lower-intensity CPX-351 + VEN in adults with newly diagnosed AML who are unfit for IC. Methods: This is an ongoing, open-label, phase 1b study (NCT04038437). Patients who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles in the dose-exploration phase (DEP) or up to 8 similar cycles in the expansion phase (EP). Patients are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Results: The data include 31 patients enrolled by 15 September 2021, with a data cutoff of 2 December 2021: 4 patients in the DEP at dose level 1 (CPX-351 20 units/m2 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle), 7 patients in the DEP at dose level 2 (CPX-351 40 units/m2 + VEN 400 mg), and a total of 20 patients in the DEP and EP at dose level 1b (CPX-351 30 units/m2 + VEN 400 mg), which was established as the recommended phase 2 dose. Patients were considered unfit for IC based on age ≥75 years (n=15) or health (Eastern Cooperative Oncology Group performance status of 2 to 3 and/or comorbidities [n=16]). Median age was 74 years (range: 60, 90); 65% were male; 77% had de novo AML; 58% had poor-risk disease; and 23% had a TP53 mutation. Nonhematologic treatment-emergent adverse events (TEAEs) in ≥20% of patients were diarrhea (26%), cough (23%), dyspnea (23%), and nausea (23%). Hematologic grade ≥3 TEAEs were reported in 17 (55%) patients; no nonhematologic grade ≥3 TEAE was reported in >10% of patients. There were no deaths by Day 30; mortality at Day 60 was 13%, with deaths due to myocardial infarction unrelated to therapy (n=1), worsening lung infection (n=1), and disease progression (n=2). Median (interquartile range) recovery times were 30 days (22, 34.5) to neutrophils ≥500/μL and 21 days (21, 27) to platelets ≥50,000/μL. Complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 16/28 (57%) patients with an evaluable remission assessment. All 16 of these patients achieved remission (CR or CRi) after the first treatment cycle. MRD negativity was achieved by 12/16 (75%) patients with CR or CRi, primarily after Cycle 1 (Cycle 1: n=8; Cycle 2: n=2; Cycle 3: n=1; Cycle 4: n=1). Survival data are not yet mature. Summary/Conclusion: Lower-intensity CPX-351 + VEN was generally well tolerated in adults with newly diagnosed AML who are unfit for IC and showed promising initial efficacy, with CR or CRi in the majority of patients.