Research on co-mutated genes in FLT3-ITD-positive acute myeloid leukemia

Abstract

Abstract Background: The FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplication) mutation is prevalent in 20%–30% of acute myeloid leukemia (AML) cases and is associated with poor prognosis, including lower complete remission rates and higher relapse risk. FLT3-ITD patients with different AML mutation genes exhibit varying prognosis. The purpose of this study is to characterize the co-mutation gene profiles of FLT3-ITD-positive AML patients. Methods:A total of 959 AML cases from January 2020 to December 2024 were included. Fragment analysis identified 275 FLT3-ITD-positive patients, and PANEL-NGS was used to obtain co-mutation gene data for these patients. The incidence of co-mutation genes and their relationship with age and AML classification were analyzed in the 275 patients. Results: Among the 275 FLT3-ITD-positive AML patients, 251 (91.27%) had detectable co-existing gene mutations, only 24 (8.73%) showed no co-mutations. The most common co-mutation gene was NPM1 (133 cases, 48.36%), followed by DNMT3A 93 cases (33.82%), WT1 44 cases (16.00%), IDH2 41 cases (14.91%), NRAS 35 cases (12.73%), and TET2 28 cases (10.18%). Co-mutations of FLT3-ITD, NPM1 and DNMT3A were found in 74 cases (26.91%). Among pediatric patients (<18 years, n=9), no NPM1 and DNMT3A co-mutations were detected. In elderly patients (≥60 years, n=54), FLT3-ITD, NPM1 and DNMT3A co-mutations were found in 19 cases (35.19%). 55 cases (25.94%) with FLT3-ITD, NPM1 and DNMT3A co-mutations were found among patients aged 18 to 60 years (n=212). According to the 2016 WHO AML classification, none of the 37 cases AML with PML::RARA/RUNX1::RUNXT1/CBFB::MYH11/MLLT3::KMT2A showed NPM1 and DNMT3A co-mutations. Among 193 AML-M5 cases, FLT3-ITD, NPM1 and DNMT3A co-mutations were detected in 66 cases (89.19%). Based on the 2024 NCCN guidelines, 53 cases (19.27%) had co-mutations with MDS-related genes (RUNX1, SRSF2, ASXL1, BCOR, U2AF1, EZH2, SF3B1, STAG2, ZRSR2), the frequency was RUNX1 (6.91%), SRSF2 (4.0%), ASXL1 (2.18%), BCOR (1.82%), U2AF1(1.45%), and EZH2(1.09%). Conclusion: Evaluating the co-mutation gene profiles of FLT3-ITD-positive AML patients can help improve prognostic assessment and guide personalized, precision treatment strategies. Keywords: Acute myeloid leukemia, FLT3 internal tandem duplication, Co-mutation genes