Venetoclax-azacitidine-chidamide plus CAG (CACAG-VEN) versus “3+7” induction chemotherapy in  Intermediate-adverse Acute Myeloid Leukemia: Efficacy and safety

Abstract Venetoclax-Azacitidine-Chidamide Plus CAG (CACAG-VEN) versus “3+7” Induction Chemotherapy in Intermediate-Adverse Acute Myeloid Leukemia: Efficacy and Safety Abstract Purpose The optimal induction regimen for intermediate-adverse acute myeloid leukemia (AML) patients is uncertain, although a standard “3+7” induction regimen and emerging strategies combining hypomethylatingagents and Bel-2 inhibitor is commonly used. Methods In this phase 2 clinical trial, we aimed to investigate the efficacy and safety of venetoclax-azacitidine in combination with chidamide and CAG (cytarabine, aclarubicin, granulocyte colony-stimulating factor), named as CACAG-VEN, in intermediate-adverse AML across 6 centers in China. Patients aged 14-75 eligible for intensive chemotherapy were randomized 1:1 to receive CACAG+VEN or “3+7” regimen. The primary endpoint was the overall response rate (ORR) after one cycle of induction therapy. Results Of 106 screened, 100 were enrolled and randomly assigned, with 50 in each group. In the intention-to-treat population, ORR was 98.0% (49/50) in the CACAG+VEN group versus 74.0% (37/50) in the “3+7” group (P < 0.001). MRD negativity after induction was 61.2% versus 61.8%, respectively. Compared with “3+7”group, CACAG+VEN showed superior ORR in patients aged ≥60 years (100.0% vs. 53.9%, P = 0.015), WBC count exceeding 50 × 109/L (100.0% vs.57.1%, P = 0.051), ELN2022 intermediate risk (100.0% vs. 73.9%, P = 0.021), and ELN2022 adverse risk (96.4% vs. 74.1%, P = 0.025). Although there were no statistically significant differences in overall survival (OS), event-free survival (EFS), or duration of response (DOR) between the two groups, the CACAG-VEN group showed a trend toward improved OS ( 1-year: 87.6%vs. 78.8%), EFS (7-year: 1.4% vs. 60.2%), and DOR (-year: 71.1% vs. 67.5%) compared to the “3+7” regimen. The most common grade 3-4 non-hematologic adverse events in both groups were febrile neutropenia and pulmonary infection, with no significant differences in both groups. It achieved faster neutrophil recovery to ≥1000/μL (median 19 vs. 20 days, P = 0.047) and earlier platelet reconstitution (≥20,000/μL: 16 vs. 18 days, P =0.001). Conclusion Among intermediate and adverse-risk AML patients, the CACAG-VEN demonstrated superior response rates over “3+7” regimen, along with faster hematologic recovery.