Venetoclax-azacitidine in combination with chidamide and CAG versus daunorubicin and cytarabine in newly diagnosed AML

Abstract Abstract Purpose The standard “3+7” daunorubicin-cytarabine (DA) induction regimen for acute myeloid leukemia (AML) demonstrates limited efficacy and unfavorable prognosis. Even with emerging strategies combining hypomethylating agents, and Bcl2 inhibitor, suboptimal outcomes persist. Through drug synergy analysis, we demonstrated that the multiple epigenetic agents combined with cytarabine and aclarubicin synergistically induced significantly faster and deeper apoptosis compared to monotherapy. This finding prompted the design of Venetoclax-Azacitidine in Combination with Chidamide and CAG (cytarabine, aclarubicin, granulocyte colony-stimulating factor), named as CACAG+VEN. Methods In this phase 3 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 newly diagnosed AML across 8 centers in China. Patients aged 14-75 eligible for intensive chemotherapy were randomized 1:1 to receive CACAG+VEN or DA regimen. The primary endpoint was the overall response rate (ORR) after one cycle of induction therapy. Results Of 176 screened, 170 were enrolled and randomly assigned, with 85 in each group. In the intention-to-treat population, ORR was 98.8% (84/85) in the CACAG+VEN group versus 75.3% (64/85) in the DA group (P < 0.001). MRD negativity after induction was 56.3% (45/80) versus 55.0% (33/60), respectively. CACAG+VEN showed superior ORR in patients aged ≥60 years (100.0% vs 66.7%, P = 0.012) acute monocytic leukemia (98.9% vs 76.9%, P = 0.020), and ELN2022 adverse risk (96.8% vs 74.1%, P = 0.012), while showing clinically meaningful trends in acute myeloid leukemia myelodysplasia-related (96.2% vs 78.6%, P = 0.055) and AML with RUNX1::RUNX1T1 (100.0% vs 69.2%, P= 0.278) compared to DA. At a median follow-up of 347 days (range, 181-639), the event-free survival (EFS) was superior in CACAG+VEN (80.0%) compared with DA group (70.1%, P = 0.0463). Trends toward prolonged overall survival (OS), extended duration of remission (DOR), and reduced cumulative incidence of relapse (CIR) were also observed in CACAG+VEN. The CACAG+VEN group showed significantly lower febrile neutropenia (56% vs 80%, P = 0.001), grade ≥3 lung infection (22% vs 38%, P = 0.030), and grade ≥3 soft tissue infection (4% vs 14%, P = 0.028) versus DA group. It achieved faster neutrophil recovery to ≥1000/μL (median 19 vs 21 days, P = 0.020) and earlier platelet reconstitution (≥20,000/μL: 15 vs 17 days, P <0.001; ≥50,000/μL: 16 vs 17 days, P =0.023). Conclusion In conclusion, CACAG+VEN demonstrated superior response rates and improved EFS over DA in newly diagnosed AML patients across different genetic groups, with superior safety. The trial was registered at ClinicalTrials.gov as #NCT06068621.