AFFILIATIONS
1 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
2 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
3 Department of Hematology, the Affiliated People's Hospital of Ningbo University, Ningbo, China
4 Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China
5 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
6 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
7 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
8 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
9 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
10 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
11 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
12 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
13 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
14 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
15 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
16 Bone marrow transplant center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
17 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
18 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
19 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
20 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
21 Linping District First People's Hospital, Hangzhou, China
22 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
23 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
24 Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
ABSTRACT
Background: Despite being the standard induction for newly diagnosed AML, the 7+3 regimen (DA) yields suboptimal remissions and substantial relapse. The VHAA regimen (venetoclax with homoharringtonine, aclarubicin, and cytarabine) showed promising phase II activity, with complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates up to 93.9%. However, no phase III randomized evidence directly comparing VHAA with DA exists. This trial aimed to compare their efficacy and safety as frontline therapy.
Methods: This multicenter, open-label, phase III randomized trial (ChiCTR2200059663) was conducted at 5 Chinese centers. Patients aged 18–60 with newly diagnosed de novo AML (excluding acute promyelocytic leukemia) and ECOG PS 0–2 were randomized 2:1 to receive VHAA (homoharringtonine 2 mg/m²/day d1–5; cytarabine 100 mg/m²/day d1–5; aclarubicin 12 mg/m²/day d1–5; venetoclax 100 mg d2, 200 mg d3, 300 mg d4–10) or DA (daunorubicin 60 mg/m²/day d1–3; cytarabine 100 mg/m²/day d1–7). Patients with partial remission (PR) and >60% blast reduction underwent reinduction; those failing to achieve composite complete remission (CRc) after two cycles were withdrawn for salvage therapy. All patients achieving CRc received high-dose cytarabine (1.5–2 g/m², every 12 hours, 6 doses total) consolidation (± venetoclax) for 3 cycles; and allogeneic hematopoietic stem cell transplantation (allo-HSCT) was recommended for intermediate- or adverse-risk patients per ELN-2022 criteria. The primary endpoint was CR, with secondary endpoints including CRc, MRD-negative CRc (<0.01%), event-free survival (EFS), overall survival (OS), and safety.
Results: Between May 2022 and February 2024, 180 patients were randomized (VHAA, n=120; DA, n=60). Baseline characteristics were balanced: median age was 42.5 years (range, 18–60) in the VHAA group vs. 47.5 years (range, 18–60) in the DA group; male sex comprised 47.5% and 43.3%, respectively; and presenting white blood cell count >30×10?/L was observed in 31.7% vs. 36.7%. According to ELN-2022 risk stratification, favorable-risk patients accounted for 45.8% vs. 41.7%, intermediate-risk 26.7% vs. 38.3%, and adverse-risk 27.5% vs. 20.0% (all P>0.05). Common molecular mutations were similarly distributed.
After one induction, VHAA yielded significantly higher CR (87.5% vs. 55.0%; P<0.001) and CRc (89.2% vs. 66.7%; P<0.001). CR benefit with VHAA was consistent across ELN risk subgroups (favorable: 96.4% vs. 72.0%, P=0.033; intermediate: 87.5% vs. 52.2%, P=0.006; adverse: 72.7% vs. 25.0%, P=0.004) and pronounced in FLT3-ITD (83.3% vs. 40.0%, P=0.034), NPM1 (100% vs. 33.3%, P=0.002), and IDH1/2-mutated (77.8% vs. 23.1%, P=0.027). MRD-negative CRc was achieved in 86.0% vs. 55.0% (P<0.001). Neutrophil recovery to >1×10?/L from the first treatment day was similar (median 19 vs. 19 days), while platelet recovery >50×10?/L from the first treatment day was significantly faster with VHAA (median 20 vs. 22 days, P=0.018). Allo-HSCT at CR1 was performed in 53.5% vs. 34.6%.
With median follow-up 35.7 vs. 37.5 months, median EFS was not reached in the VHAA group vs. 23.8 months in the DA group; 3-year EFS was 69.7% (95% CI, 60.5–77.1) vs. 47.5% (95% CI, 34.3–59.6), with a significant HR of 0.474 (95% CI, 0.280–0.805; P=0.002). This EFS advantage was predominantly driven by the adverse-risk ELN subgroup (HR, 0.254; 95% CI, 0.089–0.724; P<0.001), with a more modest trend in the favorable-risk subgroup (HR, 0.479; 95% CI, 0.181–1.269; P=0.093). Median OS was not reached in either arm; 3-year OS rates were 78.8% vs. 72.0% (HR 0.750; 95% CI, 0.390–1.443; P=0.368). In subgroup analyses by ELN risk, the HRs for OS (VHAA vs. DA) were: favorable, 0.461 (95% CI, 0.151–1.409; P=0.124); intermediate, 1.591 (95% CI, 0.510–4.971; P=0.444); and adverse, 0.594 (95% CI, 0.177–1.997; P=0.379), suggesting a potential superiority trend in both low- and high-risk categories. Cumulative relapse rates were 15.8% in the VHAA vs. 28.8% in the DA, and overall mortality was 20.8% vs. 26.7%, respectively. Grade ≥3 adverse events were predominantly myelosuppression; non-hematologic toxicities and 30-day mortality (2.5% vs. 1.7%, P>0.999) were comparable between groups. Further analysis results will be presented at the ASH meeting.
Conclusions: In this first phase III trial, VHAA induction significantly improved CR, MRD-negative remission, and EFS versus DA in newly diagnosed AML, with manageable toxicity.