AFFILIATIONS
1 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
2 Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
3 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
4 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
5 The First Affiliated Hospital of Guangxi Medical University, Nanning, China
6 Weifang people’s hospital, Weifang, China
7 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
8 The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
9 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
10 The Affiliated People's Hospital of Ningbo University., Ningbo, China
11 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
12 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
13 Guangdong Provincial People's Hospital, Guangzhou, China
14 The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
15 Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
16 Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, the Second Hospital of Dalian Medical University, Dalian, China
17 Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing, China
18 Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, China
19 The Third Affiliated Hospital of Soochow University, Changzhou, China
20 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
21 The First Affiliated Hospital of Ningbo University, Ningbo, China
22 Third Hospital of Shanxi Medical University, Taiyuan, China
23 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
24 AbbVie Pharmaceutical Trading(Shanghai) Co., Ltd, Shanghai, China
25 AbbVie Pharmaceutical Trading(Shanghai) Co., Ltd, Shanghai, China
26 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
27 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
28 National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, Suzhou, China
ABSTRACT
Introduction
Patients (pts) in the adverse-risk category who received intensive chemotherapy (IC) have historically shown low complete remission (CR) rates and poor outcomes under the 2022 European Leukemia Net (ELN) genetic risk stratification. In a single-arm, phase 2 study (NCT04752527) from our group, venetoclax plus decitabine (VEN-DEC) achieved a 93% response rate in young adult pts with newly diagnosed (ND) ELN-adverse-risk AML (Blood, 2023). In our phase 2b randomized controlled trial (NCT05177731) comparing VEN-DEC with idarubicin-cytarabine (IA-12) in ND AML, a similar finding was observed in the adverse-risk subgroup: CRc rates were 91% (95% CI, 72%–99%) with VEN-DEC versus 42% (95% CI, 20%–67%) with IA-12 (P = 0.017) (Blood, 2025). This study aimed to provide higher-level evidence on whether venetoclax plus azacitidine (VA) improves outcomes compared with standard “7+3” IC (daunorubicin plus cytarabine; DA) in young, treatment-naive pts with adverse-risk AML.
Methods
This phase 2b, randomized, controlled, open-label, multicenter trial (NCT05939180) enrolled adults (18–64 years) with ND AML (WHO 2022) and adverse-risk per ELN 2022, identified using rapid targeted DNA/RNA sequencing (≤72h), who were eligible for intensive chemotherapy. Eligible patients were randomized 1:1, stratified by TP53 mutation and KMT2A rearrangement, to receive VA (venetoclax 400 mg QD D1–28 + azacitidine 75 mg/m² D1–7) or DA (daunorubicin 60 mg/m² D1–3 + cytarabine 100 mg/m² D1–7) in 28-day cycles. Patients achieving CR/CRi or morphologic leukemia-free marrow after cycle 1 could proceed to consolidation; non-responders could receive a second induction cycle. Allo-HSCT was permitted after CR. Primary endpoint was composite CR rate (CR+CRi) after cycle 1. Secondary endpoints included AEs, DOR, EFS, and OS.
Results
Across 26 centers in China, between April 7, 2024, and May 14, 2026, 1,189 pts were screened by a rapid diagnosis and high-throughput sequencing platform in the central laboratory; of these, 866 had confirmed ND AML, and 225 had ELN-2022 adverse-risk features. A total of 119 patients from 17 centers were randomized and included in the intention-to-treat (ITT) population (59 in the VA group and 60 in the DA group), consisting of 62 males and 57 females with a median age of 49 years (range, 18–64 years). Baseline characteristics were well-matched between groups. No significant intergroup differences were observed in the frequencies of high-risk aberrations, including TP53 mutations (7/59 vs. 8/60), KMT2A rearrangements (9/59 vs. 14/60), as well as alterations in MDS-related genes, spliceosome components, chromatin modifiers, DNA methylation-related genes (all P > 0.05), indicating that randomization achieved satisfactory baseline balance.
By the cut-off date of June 30, 2026, the median follow-up for the entire cohort was 9.0 (0.2–23.3) months. In the ITT population, the CRc rate by cycle 1 end was 62.7% (95%CI, 49-75%) in the VA group vs. 40.0% (95%CI, 28-53%) in the DA group ( P=0.013), demonstrating a superior CRc rate for the VA regimen. Subgroup analyses showed significant VA superiority in patients with chromatin mutations (64.0% vs 24.0%, P=0.004), and DNA methylation mutations (80.0% vs 38.9%, P=0.010). Significant benefits were also seen in most wild-type subgroups, while no mutation-positive subgroup significantly favored DA.
Grade (G)3/4 therapy-related adverse events in ≥10% were mainly hematologic and at similar rates across arms. G3/4 lung infections and sepsis occurred in 12% and 4.5% of VA, and 32% and 10% of DA pts. Tumor Iysis sndrome occurred in 2 patients in the VA group (with 1 case requiring CRRT) and in 1 patient in the DA group. 30- and 100-day mortality on the VA arm were 0% and 3.4%, vs 1.7% and 6.7% in the DA arm, respectively.
54.2% (32/59) in the VA group and 56.7% (34/60) in the DA group proceeded to allo-HSCT. With a median follow-up of 9.0 months, the median remission duration and OS have not been reached. Landmark 6-month OS was numerically higher in the VA arm (96.1%) versus the DA arm (90.1%), with an HR of 0.43 (95%CI 0.13–1.39, Log-rank P=0.144).
Conclusions
VA significantly improved CRc after cycle 1 versus DA in young adults with adverse-risk AML, with favorable safety and low early mortality. Survival advantage was numerically observed but not yet significant at 9.0-month follow-up. VA represents a promising frontline option for this high-risk population.