Intermediate‑dose cytarabine is noninferior to high‑dose cytarabine for AML consolidation: A systematic review and meta‑analysis

Abstract Introduction: High-dose cytarabine (HiDAC) has long been the standard for consolidation in acute myeloid leukemia (AML) but is associated with substantial toxicity. Recent European LeukemiaNet (ELN 2017/2022) guidelines favor intermediate-dose cytarabine (IDAC). Given limited randomized evidence, we conducted a systematic review and meta-analysis comparing HiDAC versus IDAC as monotherapy for AML consolidation.Methods: We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library (Jan 2010–Jun 2025) for randomized or controlled observational studies comparing HiDAC and IDAC in patients ≤65 years receiving cytarabine monotherapy for consolidation, with ≥12-month median follow-up and reporting overall survival (OS) and relapse-free survival (RFS). Two reviewers independently extracted data. Pooled hazard ratios (HR) with 95% confidence intervals (CI) were estimated using a DerSimonian-Laird random-effects model. Analyses were performed with Review Manager (v5.4.1). This systematic review was registered with PROSPERO and is reported in accordance with the Cochrane and PRISMA 2020 guidelines. Results: Six studies including 2,621 newly diagnosed AML patients were analyzed: one randomized trial (Backbone InterGroup-1) and five non-randomized controlled studies (Kolla et al., 2021; Chanswangphuwana et al., 2022; Ravikumar et al., 2021; Hao et al., 2024; Hanoun et al., 2023). Most patients received standard 7+3 induction. Median age was 48 years; 50% were male; cytogenetic risk was favorable in 36%, intermediate in 46%, and adverse in 15%; 7.6% had core-binding factor (CBF) AML. HiDAC (2 to ≤3g/m² twice daily) and IDAC (≥1 to ≤2g/m² twice daily) were given on days 1, 3, and 5 or 1–3 for a median of 3 cycles (range, 1–4). HiDAC was used in 1,663 patients (63.5%). The weighted median follow-up was 20.7 months (range, 16–64.8). In the pooled analysis, no significant differences were observed in OS between IDAC and HiDAC (HR, 1.04; 95% CI, 0.82–1.32; p = 0.75; I² = 44%), nor in RFS (HR, 1.17; 95% CI, 0.89–1.54; p = 0.26; I² = 65%). Because 50% of patients in Kolla et al. had CBF AML—a subgroup excluded in two studies (Backbone InterGroup 1 and Chanswangphuwana et al.)— we performed a sensitivity analysis excluding this study. This analysis confirmed no significant differences in OS (HR 0.96, 95% CI 0.83–1.11; p=0.58; I²=0%) or RFS (HR 0.99, 95% CI 0.86–1.13; p=0.85; I²=0%), with complete resolution of heterogeneity. Whether the apparent HiDAC benefit in Kolla et al. reflects the high CBF prevalence remains uncertain. All studies reporting safety showed fewer adverse events with IDAC. Statistically significant reductions were seen for infectious events (Ravikumar et al., Hanoun et al.), septic shock (Chanswangphuwana et al.), and myelosuppression (Hunault et al.).Conclusion: This meta-analysis reinforces that IDAC consolidation is noninferior to HiDAC for AML in terms of survival, with a superior safety profile. Subgroup differences, particularly in CBF AML, require further investigation.