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).