AUTHORS
ZePing Zhou, MD, Yaxian Tan, MD2, Xingli Zhao, MD3, Xiaohui SUO, MD4, Guanchen Bai5, Yanliang Bai, PhD6, Yunya Luo7, Lan Mei8, Xinxiao Lu9, Linyu Yuan10, Congcong Zhang11, Yinling Li12, Sifeng Gao13, Jilei Zhang14, Heng Li, MD15, Hongling Peng, MD, PhD16, Pengxiang Guo17, Yingchang Mi, MD18, Kaiqi Liu19
AFFILIATIONS
1 The Second Affiliated Hospital of Kunming Medical University, kunming, China
2 The Second Affiliated Hospital of Kunming Medical University, kunming, China
3 Department of Hematology, Oncology Center, Tianjin People's Hospital, Tianjin, China
4 Department of Hematology, Handan Central Hospital, Hebei, China
5 Department of Hematology, The Affiliated Tai'an City Central Hospital of Qingdao University, Shandong, China
6 Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, China
7 Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
8 The Department of Hematology, Guangxi Academy of Medical Sciences & The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
9 Department of Hematology, Oncology Center, Tianjin People's Hospital, Tianjin, China
10 Department of Hematology, Oncology Center, Tianjin People's Hospital, Tianjin, China
11 Department of Hematology, Handan Central Hospital, Hebei, China
12 Department of Hematology, Handan Central Hospital, Hebei, China
13 Department of Hematology, The Affiliated Tai'an City Central Hospital of Qingdao University, Shandong, China
14 Department of Hematology, The Affiliated Tai'an City Central Hospital of Qingdao University, Shandong, China
15 Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
16 Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
17 Guizhou Provincial People’s Hospital, Guizhou, China
18 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
19 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
ABSTRACT
Background: Azacitidine plus venetoclax (AZA-VEN) is the NCCN-recommended first-line regimen for older patients with AML ineligible for intensive chemotherapy, yet outcomes remain suboptimal, particularly in adverse-risk disease. Venetoclax combined with 3-day multi-frequency decitabine (DEC3-VEN) uses a novel schedule (decitabine 20 mg/m² every 8 hours) designed to maximize S-phase DNA incorporation and venetoclax synergy. We previously reported encouraging preliminary activity, here we present the final analysis of this randomized trial comparing DEC3-VEN head to head against AZA-VEN.
Methods: Treatment-naïve patients aged ≥60 years with AML ineligible for intensive chemotherapy were randomized 1:1 to DEC3-VEN (venetoclax 400 mg daily, days 1–14; decitabine 20 mg/m² q8h, days 2–4) or standard AZA-VEN (venetoclax 400 mg daily, days 1–28; azacitidine 75 mg/m² daily, days 3–9). The primary endpoint was event-free survival (EFS). Secondary endpoints included composite complete remission (cCR), measurable residual disease (MRD) by multiparameter flow cytometry, overall survival (OS), and safety.
Results: From December 2023 to December 2025, a total of 154 patients were enrolled from 10 centers across different provinces in China and randomly assigned (1:1) to the DEC3-VEN group (n=77) or the AZA-VEN group (n=77). Eight patients (five in the DEC3-VEN group and three in the AZA-VEN group) withdrew consent before treatment initiation, leaving 146 patients received treatment (DEC3-VEN, n=72; AZA-VEN, n=74). The median age was 72.5 years in the DEC3-VEN group (61.1% male) and 71 years in the AZA-VEN group (68.0% male). According to the ELN 2022 risk classification, in the AZA-VEN group, 13 (17.6%) were favorable, 21 (28.4%) intermediate, and 40 (54.0%) adverse, in the DEC3-VEN group, 9 (12.5%) were favorable, 17 (23.6%) intermediate, and 46 (63.9%) adverse.
Four patients (5.6%, 4/72) in the DEC3-VEN group and six (8.1%, 6/74) in the AZA-VEN group died during induction therapy, leaving 68 patients in each group evaluable for efficacy.The cCR rate was significantly higher with DEC3-VEN than with AZA-VEN (79.4% [54/68] vs. 55.9% [38/68]; risk difference [RD], 23.5 percentage points; 95% CI, 6.8 to 40.2; P=0.006) after one induction cycle. Of these, 75.0% (51/68) in the DEC3-VEN group and 45.6% (31/68) in the AZA-VEN group achieved CR (RD, 29.4 percentage points; 95% CI, 14.3 to 44.5; P < 0.001).Among patients who achieved cCR, MRD negativity after induction was observed in 74.1% (40/54) in the DEC3-VEN group and 52.6% (20/38) in the AZA-VEN group (RD, 21.5 percentage points; 95% CI, 2.2 to 40.7; P=0.033).At a median follow-up of 18.0 months (range, 7.4-30.0), DEC3-VEN significantly prolonged EFS (median, 12.4 vs 7.2 months; HR for AZA-VEN vs DEC3-VEN, 1.66; 95% CI, 1.11 to 2.48; P = 0.014) and OS (median, 12.8 vs 9.4 months; HR for AZA-VEN vs DEC3-VEN, 1.57; 95% CI, 1.03 to 2.40; P = 0.036). DEC3-VEN was associated with more grade ≥3 hematologic toxicity (anemia 93.1% vs 66.2%, P<0.001; thrombocytopenia 86.1% vs 70.3%, P=0.020) but substantially fewer gastrointestinal adverse events (nausea 13.9% vs 35.1%, P=0.002; anorexia 16.7% vs 44.6%, P=0.010).
Conclusion: In this randomized trial, DEC3-VEN significantly improved remission rates, MRD clearance, EFS, and OS compared with AZA-VEN, with a distinct and manageable toxicity profile. These final results support DEC3-VEN as a new standard-of-care candidate for older, unfit patients with newly diagnosed AML.
DISCLOSURES
ZePing Zhou, MD: No relevant conflicts of interest to declare.