Optimal dose and duration of venetoclax for induction therapy in acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis

Abstract Background Venetoclax, a selective BCL-2 inhibitor, has become a key component of induction therapy for newly diagnosed acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Despite its expanding use, the optimal dose and duration of venetoclax remain undefined, with wide variability across clinical trials and real-world practice. Establishing evidence-based guidance is essential to maximizing clinical benefit while minimizing toxicity.Aims This systematic review and meta-analysis aimed to evaluate the efficacy and safety of varying venetoclax doses and durations during induction therapy for AML and MDS, with the goal of identifying treatment schedules associated with optimal outcomes.Methods A comprehensive literature search of PubMed, Cochrane, and ClinicalTrials.gov was conducted in May 2025, in accordance with the PRISMA guidelines. Of 279 identified records, 54 original studies reporting adult AML/MDS patients treated with venetoclax-based induction regimens were included. Data on demographics, venetoclax dosing and duration, risk stratification, response rates, survival outcomes, and adverse events were extracted. Pooled estimates were calculated using a random-effects model with the 'meta’ package in R.Results A total of 4,206 patients were included (AML: 4,153; MDS: 53). Among 3,099 patients with reported sex, 1417 (45.7%) were male, and the median age across studies ranged from 34 to 80 years. In AML, 17.6% of patients had favorable-risk disease, 44.6% had intermediate-risk disease, and 40.6% had adverse-risk disease. Most studies utilized venetoclax at a dose of 400 mg, with a median of 2–7 treatment cycles, with two being most common. Across all studies, pooled response rates were: Composite Complete Remission (CCR) 75% (95% CI: 68.9–80.2), Complete Remission 56.7% (95% CI: 49.8–63.4), Incomplete Complete Response (iCR) 17% (95% CI: 11–24), and Overall Response Rate (ORR) 77.3% (95% CI: 72–82); all p < 0.0001. Reported median overall survival (OS) ranged from 5 to 22.5 months and disease-free survival (DFS) from 4.7 to 26.6 months. Duration-specific analysis showed that treatment administered for 7–14 days resulted in the highest response rates: CCR 86% (95% CI: 81–90), CR 75% (95% CI: 65–83), iCR 13% (95% CI: 1–64), and ORR 87% (95% CI: 82–90), with non-significant heterogeneity (p = 0.19–0.22). In contrast, longer durations were associated with reduced response. For days 14–21, the CCR, CR, and ORR were 72% (95% CI: 56–84), 55% (95% CI: 47–63), and 72% (95% CI: 57–84) while for days 21–28 were 69% (95% CI: 61–76), 48% (95% CI: 39–57), and 72% (95% CI: 63–80), respectively; with all p < 0.0001 unless otherwise specified. Duration-specific analysis revealed distinct toxicity profiles across treatment intervals. Between days 7–14, the pooled incidence of febrile neutropenia was highest at 83% (95% CI: 61–94, p = 0.004), while neutropenia reached 98% (95% CI: 93–100, p = 0.89). During days 14–21, the incidence of neutropenia declined to 80% (95% CI: 54–93, p = 0.169). A further decrease was observed between days 21–28, with febrile neutropenia at 43% (95% CI: 39–48, p = 0.23) and neutropenia at 64% (95% CI: 44–80, p < 0.0001). Overall, the pooled incidence rates across all durations were 77% for neutropenia (95% CI: 64–85, p < 0.0001), 50% for febrile neutropenia (95% CI: 41–58, p < 0.0001), and 68% for infections (95% CI: 48–82, p < 0.0001). Febrile neutropenia could not be analyzed in studies with duration 14-21 days due to insufficient data.Conclusion This meta-analysis suggests the highest efficacy of venetoclax with the treatment scheduled of 7–14 days at a dose of 400mg, with diminishing benefit observed beyond this duration. Interestingly, the incidence of neutropenia and febrile neutropenia was highest in the same schedule, with a gradual decline thereafter. These results support a time-sensitive therapeutic window and underscore the need for prospective trials to validate optimal treatment schedules tailored to disease risk and patient characteristics.