Comprehensive Analysis of FLT3-Mutated Patients with Acute Myeloid Leukemia with Updated 2022 European LeukemiaNet Recommendations: Insights from the Turkish AML Registry Project

Abstract

Background: This study aimed to evaluate the prognostic significance and clinical impact of the revised 2022 European LeukemiaNet (ELN) classification for acute myeloid leukemia (AML), focusing particularly on patients harboring fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. Methods: A retrospective, multicenter observational study was conducted by the Turkish Society of Hematology-Acute Leukemias Working Group, analyzing 312 adult patients newly diagnosed with AML from January 2012 to December 2022. Patients with acute promyelocytic leukemia were excluded. FLT3-ITD mutations were detected using polymerase chain reaction and, when available, next-generation sequencing. Patients were classified according to the 2017 ELN risk stratification, and FLT3-ITD-positive cases were reclassified based on the updated 2022 ELN criteria. Endpoints were complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results: FLT3-ITD mutations were identified in 54 (17.3%) patients. According to the 2022 ELN classification, 29 patients previously categorized as the favorable (n = 6) or adverse-risk (n = 23) groups were reclassified into the intermediate-risk group, highlighting the substantial impact of removing the FLT3-ITD allelic ratio from risk stratification. With a median follow-up of 31.8 months, OS significantly differed among the 2017 ELN favorable-, intermediate-, and adverse-risk categories (not reached, 21.6 months, and 9.5 months, respectively, p < 0.001). FLT3-ITD-positive patients demonstrated significantly inferior DFS (p = 0.038) and OS (p = 0.009) compared to FLT3-ITD-negative patients. In patients achieving first CR, allogeneic hematopoietic stem cell transplantation (HSCT) improved OS in intermediate-risk (p = 0.003), showed a trend in adverse-risk (p = 0.098), and no benefit in favorable-risk (p = 0.351). Among reclassified FLT3-ITD-positive patients, survival outcomes aligned closely with the original intermediate-risk group defined by the 2017 ELN, supporting the rationale behind the ELN revision. Conclusions: Our findings validate the prognostic utility of the revised 2022 ELN guidelines, especially regarding FLT3-ITD-positive AML, emphasizing that the exclusion of the FLT3-ITD allelic ratio yields a more biologically consistent risk categorization. Furthermore, the data support tailored ELN-based risk stratification for older AML patients. Given the modest benefit of HSCT in adverse-risk patients, future refinements should further stratify this group to address their unmet therapeutic needs and enhance survival outcomes. Trial registration: The study was registered at ClinicalTrials.gov (NCT05979675). © 2025 Elsevier B.V., All rights reserved.