Aml-757 venetoclax with chemotherapy for remission induction in aml patients: the phase ib/ii (rapid ven) study

Abstract

Introduction Venetoclax decreases the apoptotic threshold and has synergistic activity with cytotoxic drugs, making it ideal for combination induction therapy (IC) in AML patients. However, optimum chemotherapy dose and schedule for this combination in the Indian population is not known. This study evaluates maximum tolerated dose of IC (daunorubicin + cytarabine) with venetoclax and early outcomes following IC. Methods Both newly diagnosed (ND) and relapsed/refractory (R/R) AML patients (FLT3/ITD excluded) with ECOG PS 0-2 are included in this single center phase Ib/II study (2023-2024). Baseline characteristics, bone marrow or peripheral blood flow cytometry, cytogenetics, and NGS reports are recorded. In phase 1b, 5 levels from -1 to 3 with varying doses of daunorubicin (45 or 60 mg/m2 for 2 or 3 days), cytarabine (100 mg/m2 SC BD for 5 or 7days), and venetoclax 100 mg (5 or 7 days with antifungal). 3 + 3 design used for dose escalation and de-escalation. Simon's 2-stage design in phase II with 2 arms (Arm A-ND [n=28] and Arm B-R/R [n=26]) will be conducted. Results Ten patients were enrolled in phase I study with first cohort at level 1 (3 patients); 2 had dose-limiting toxicity (DLT) and deescalated to second cohort at level 0 with 3 patients (1 DLT). By adding second and third cohort, 1 of 6 patients had DLT. The recommended phase II dose was 2 days daunorubicin + 5 days cytarabine + 5 days venetoclax. The study proceeded to phase II with 2 arms. A total of 24 patients enrolled in phase II to date. Baseline characteristics: median age 35 (range: 16-66); male predominance (n=26). Median blast count, 45% (range: 21-95%). ELN risk is favorable, 25%; intermediate, 38%; adverse, 32%. Most common mutations are RUNX1-RUNX1T1 (24%), NPM1 (24%), and IDH2 (17%). Induction mortality (IM) is 23% (n=8/34); 5 of 34 patients are currently on induction therapy; 19 of 21 (90.4%) patients are in complete remission (CR), and 18 of 21 (85%) patients are MRD-. The study is in progress. Conclusions Adding venetoclax to standard therapy has commendable CR rates without increasing IM. Venetoclax not more than 5 days with 2 + 5 (daunorubicin and cytarabine) will be the suitable regimen.