Safety and efficacy of semi-dose venetoclax plus azacitidine in unfit acute myeloid leukemia patients in China: a real-world single-center study.

Abstract

Acute myeloid leukemia (AML) carries a poor prognosis in elderly or medically unfit patients, with median overall survival (OS) of only 7-8 months for those ineligible for intensive chemotherapy. While venetoclax (VEN) combined with azacitidine (AZA) has become a standard therapy, real-world evidence indicates that Asian patients experience higher VEN exposure and toxicity with the standard 400 mg/day dose. This retrospective study aimed to evaluate the efficacy and safety of a reduced-dose regimen (VEN 200 mg/day + AZA) in frail/elderly Chinese AML patients deemed unfit for intensive therapy. We analyzed 14 patients (13 newly diagnosed, 1 relapsed; median age 71.5 years) treated at Zhejiang University Hospital (May 2020-May 2024). All had ECOG status ≥ 3 (64.3%) or comorbidities (71.4%), and 57.1% were classified as adverse-risk by ELN 2022 criteria. Treatment comprised AZA (75 mg/m², days 1-7) and VEN (200 mg/day, days 1-28, in absence of CYP3A4 inducer). Response to treatment was evaluated by bone marrow biopsy for minimal residual disease (MRD). Toxicity was graded per CTCAE v5.0. Survival and trough VEN concentrations were analyzed using Kaplan-Meier and descriptive statistics. All patients (100%) achieved CR/CRi, with a median time to MRD negativity of 1.45 months. Median OS was not reached (> 24.6 months), with 2-year OS and EFS rates of 61.5% and 53.8%, respectively. Adverse-risk patients (42.9%) showed 50.0% survival beyond 21.8 months. Trough VEN concentrations (median 487.7 ng/mL) exceeded therapeutic thresholds (~ 500 ng/mL), confirming adequate exposure. Hematologic toxicity was reduced versus historical full-dose data: grade ≥ 3 thrombocytopenia (21.4% vs. 24-89.5%), febrile neutropenia (35.7% vs. 42.9-78.9%), and anemia (50.0% vs. 70-100%). No VEN dose modifications, tumor lysis syndrome, or 60-day mortality occurred. The semi-dosed VEN-AZA regimen (200 mg/day) demonstrated unprecedented efficacy (100% CR/CRi, median OS > 24.6 months) and a favorable safety profile in frail Chinese AML patients. Reduced toxicity without compromised efficacy supports its use in this population, likely due to optimized pharmacokinetics in Asian patients. These findings challenge the necessity of standard VEN dosing and highlight 200 mg/day as a viable, potentially superior strategy for this demographic.