Venetoclax and Decitabine Compared with Standard Intensive Chemotherapy As Induction Therapy in Newly Diagnosed Acute Myeloid Leukemia: Updated Results of a Multicenter, Randomized, Phase 2b Trial
Authors: Lu Jing , Xue Shengli , Wang Ying , He Xuefeng , Hu Xiaohui , Miao Miao , Zhang Yang , Tang Zaixiang , Xie Jundan , Yang Xiaofei , Xu Mingzhu , Shen Yaoyao , Du Feng , Wu Qian Vicky , Xue Mengxing , Wang Yun , Deng Ailing , Dou Xueqing , Dai Haiping , Wu Depei , Chen Suning 
Published: December 2024

Introduction
Venetoclax plus hypomethylating agents (VEN+HMA) has shown remarkable efficacy in elderly and unfit AML patients. However, prospective studies comparing VEN+HMA to standard intensive chemotherapy in young and fit AML patients are lacking. We conducted a phase 2 study to compare the efficacy and safety of VEN+HMA versus the standard 7+3 regimen in newly diagnosed AML patients eligible for intensive chemotherapy. Preliminary results were reported at ASH 2023 (#970). The study, now complete with increased sample size and extended follow-up, presents the final analysis.
Methods
In this multicenter, randomized, open-label, controlled phase 2 trial, newly diagnosed Chinese AML patients aged 18-59 years and eligible for intensive chemotherapy were randomly assigned, in a 1:1 ratio to receive either venetoclax plus decitabine (VEN-DEC) or the idarubicin plus cytarabine (IA-12) as induction therapy. Patients in the VEN-DEC arm received venetoclax (orally, once daily, for 28 days, target dose 400 mg) and decitabine (20 mg/m² intravenously on days 1-5). Patients in the IA-12 arm received intravenous idarubicin (12 mg/m² on days 1-3) and cytarabine (100 mg/m² on days 1-7). The primary endpoint was composite complete remission (CRc), including complete remission and complete remission with incomplete hematologic recovery, aiming to demonstrate the non-inferiority of VEN-DEC as induction therapy compared to IA-12 with a non-inferiority margin of 5% and a one-sided type 1 error of 2.5%. Secondary endpoints included the incidence of grade 3 or worse infections during induction treatment, duration of severe myelosuppression, event-free survival (EFS), overall survival (OS), and the measurable residual disease (MRD) negativity rates post-induction therapy. The exploratory endpoint was the efficacy of the two treatment regimens in cytogenetic subgroups. The study was registered on ClinicalTrials.gov (NCT05177731), and the data cut-off date was 30 April, 2024.
Results
The intention-to-treat population comprised 188 patients (94 in each group). The median age was 45 years in the VEN-DEC group and 40 years in the IA-12 group. Composite complete remission was observed in 84 (89%) of 94 patients in the VEN-DEC group versus 74 (79%) of 94 patients in the IA-12 group (test for non-inferiority, p=0.0021). VEN-DEC demonstrated non-inferiority to IA-12 at the 2.5% significance level. The difference in CRc between VEN-DEC and IA-12 was estimated to be 10.6% (95% CI 0.2 to 21.3). The rate of MRD negativity in CRc patients after induction therapy was 80% in both the VEN-DEC (67/84) and the IA-12 groups (59/74). Subgroup analysis of CRc rates showed that compared to IA-12, patients aged ≥40 years (91% vs 75%), with ELN-2022 adverse risk factors (91% vs 42%), and with epigenetic modifier mutations (91% vs 67%) benefited more from VEN-DEC, whereas the RUNX1::RUNX1T1subgroup responded better to IA-12 (44% vs 88%).
Fewer patients in the VEN-DEC group experienced grade 3 or worse infections compared to the IA-12 group (30 [32%] vs 63 [67%], χ² test, p&lt;0.001). Key grade 3 or worse infections included pneumonia (16% in the VEN-DEC group vs 32% in the IA-12 group), sepsis (7% vs 25%), and septic shock (1% vs 6%). 82% of patients in the VEN-DEC group and 93% in the IA-12 group experienced grade 3-4 hematologic adverse events. The median duration of severe neutropenia (&lt;0.5×109/L) was longer in the VEN-DEC group (23 days, IQR 17-28) compared to the IA-12 group (19 days, IQR 16-23) (p=0.001). Conversely, the median duration of severe thrombocytopenia (&lt;25×109/L) was shorter in the VEN-DEC group (13 days, IQR 0-20) compared to the IA-12 group (19 days, IQR 14-26) (p&lt;0.001).
At a median follow-up of 12.1 months (range, 0.33 to 26.5), the median survival time was not reached in either group, with no significant difference in EFS (hazard ratio, HR=0.91, p=0.714) or OS (HR=1.15, p=0.705). However, in the VEN-DEC group, patients with CEBPAbZIP had a 1-year RFS rate of 52.5% (95% CI 33.2 to 83.0), significantly lower than 85.1% (95% CI 68.0 to 100) in the IA-12 group (HR for relapse or death, 5.43; 95% CI 1.14 to 25.75; p=0.017).
Conclusions
In newly diagnosed adult patients under 60 years old who are eligible for intensive chemotherapy, VEN+DEC showed comparable efficacy but improved safety compared to the standard 7+3 regimen. However, caution is warranted when using VEN+DEC in AML patients with RUNX1::RUNX1T1 or CEBPAbZIP mutations.