Impact of c-KIT and FLT3 mutations on survival outcomes in core-binding factor acute myeloid leukemia: A systematic review and meta-analysis

Abstract

Abstract Background: Core-binding factor acute myeloid leukemia (CBF-AML) is generally considered a favorable-risk subtype; however, prognosis varies based on co-occurring genetic alterations. Among these, c-KIT and FLT3 mutations have been proposed as adverse prognostic markers, though data remain inconsistent. We performed a systematic review and meta-analysis to clarify the prognostic impact of c-KIT and FLT3 mutations in CBF-AML, with subgroup analysis according to cytogenetic subtype [t(8;21) vs. inv(16)]. Methods: All observational studies including CBF-AML patients identified from Embase, PubMed, and Cochrane Library were evaluated. Eligible studies reported hazard ratios (HR) with 95% confidence intervals (CI) for overall survival (OS), disease-free survival (DFS), event-free survival (EFS), leukemia-free survival (LFS), relapse-free survival (RFS), or cumulative incidence of relapse (CIR). The generic inverse variance method was used for pooling. Subgroup analyses were conducted by cytogenetic subtype and by concomitant gene mutation (c-KIT, FLT3-ITD, and FLT3-TKD). Results: Seventeen studies met the inclusion criteria. Presence of c-KIT mutation was associated with significantly worse outcomes, including decreased OS (pooled HR 2.02; 95% CI 1.52–2.67; I² = 59%) and RFS (HR 1.89; 95% CI 1.44–2.50; I² = 57%), as well as increased CIR (HR 2.24; 95% CI 1.42–3.55; I² = 45%). This effect was primarily driven by the t(8;21) subgroup, where c-KIT mutations were strongly associated with inferior OS (HR 2.85; 95% CI 1.65–4.93; I² = 69%), EFS (HR 2.60; 95% CI 1.81–3.74; I² = 59%), and CIR (HR 2.43; 95% CI 1.46–4.05; I² = 37%). In contrast, among patients with inv(16), c-KIT mutations were not significantly associated with OS (HR 1.30; 95% CI 0.73–2.29; I² = 37%), EFS (HR 1.22; 95% CI 0.71–2.07; I² = 4%), or CIR (HR 1.54; 95% CI 0.88–2.69; I² = 0%). FLT3 mutations showed no significant prognostic impact, with pooled HRs for OS of 1.28 (95% CI 0.83–1.98; I² = 25%) and for RFS of 1.32 (95% CI 0.91–1.92; I² = 31%), and no difference between ITD and TKD subtypes. Conclusion: This meta-analysis demonstrates that c-KIT mutations, particularly in patients with t(8;21) CBF-AML, are strongly associated with inferior survival and higher relapse rates, whereas FLT3 mutations do not significantly impact outcomes. These findings highlight the need for risk-adapted therapeutic strategies in CBF-AML, with consideration for more intensive or targeted approaches in c-KIT–mutated t(8;21) patients.