Abstract Background: Acute myeloid leukemia (AML) is characterized by significant heterogeneity, with cytogenetic and molecular genetic features, playing a crucial role in determining prognosis and guiding clinical decision-making. In AML, the incidence of FLT3 mutations (FLT3mut) is approximately 30%, with FLT3-ITD mutations (FLT3-ITDmut) accounting for about 25% and FLT3-TKD mutations (FLT3-TKDmut) comprising 5% to 10%. Currently, FLT3-ITD has been established as an independent adverse prognostic factor, while the prognostic significance of FLT3-TKD remains controversial. We aimed to describe the prognostic factors for newly diagnosed (ND) AML with FLT3-TKDmutin a large cohort of patients (pts). Methods: Retrospective analysis including all pts with AML who received frontline therapy at East China Leukemia Alliance (ECLA), from 08/2010 - 3/2025. A total of 2015 pts of ND AML were accrued, of which 107 pts were AML with FLT3-TKDmut. All pts were treated with a variety of treatment regimens, and comprehensive cytogenetic analysis and next-generation sequencing (NGS) were performed. Overall survival (OS) and event free survival (EFS) were computed using the Kaplan-Meier method and compared using log-rank test and multivariate analysis was done using the Cox proportional hazards regression model. Results: Among the 107 pts (5.3%) with detectable FLT3-TKDmutat diagnosis, the impact of initial treatment response, consolidation therapy selection on prognosis, and subgroup analysis based on whether transplantation was performed were evaluated. The median age was 55 years, the median follow-up was 1.2 years, and 45.8% of the pts were male. According to the ELN 2022 recommendations, 30 (28.0%) pts were in favorable-risk; 48 (44.9%), intermediate-risk; and 29 (27.1%), adverse-risk. FLT3-TKDmut significantly co-occurred with NPM1 (34.6%), DNMT3A (25.2%), WT1 (24.3%), NRAS (21.5%), FLT3-ITD (15.9%), TET2 (15.9%), KIT (14.0%), CBFβ-MYH11 (11.2%) and less frequently with AML1-ETO (7.5%). In all patients, 68 pts (63.6%) received intensive chemotherapy (IC) vs. 39 (36.4%) who received hypomethylating agents plus venetoclax (HMA + VEN) (P = 0.089). The median OS was 34.0 months (95% CI 9.909 - 58.091) and median EFS was 16.7 months (95% CI 8.136 - 25.397). A total of 79.2% pts achieved complete remission (CR) at the end of induction, while 49.1% achieved measurable residual disease (MRD) by multiparametric flow cytometry (MFC) 0.1%. Achieving CR following induction was substantially linked to improved OS (HR 0.149, 95% CI 0.081 - 0.272, P 0.001) and EFS (HR 0.242, 95% CI 0.139 - 0.423, P 0.001) for all pts with FLT3-TKDmut. Furthermore, we observed that pts achieving MRD 0.1% after induction exhibited significantly superior OS (HR 3.132, 95% CI 1.665 - 5.891, P 0.001) and EFS (HR 1.833, 95% CI 1.075 - 3.128, P = 0.023) compared with those with MRD ≥ 0.1%. Among the entire cohort, 33 pts (30.8%) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), 2 underwent autologous HSCT, and 72 did not receive any transplant. We conducted additional analyses of OS and EFS to delineate the prognostic significance of co-mutation and consolidation in pts with FLT3-TKDmut. Consolidation with chemotherapy alone was associated with markedly inferior OS (P 0.001) and EFS (P = 0.015) compared with HSCT. Interestingly, harboring CBFβ-MYH11mut demonstrated significantly superior survival (No allo-HSCT group: OS P = 0.112, EFS P = 0.050), whereas those who underwent allo-HSCT ended up with inferior results (allo-HSCT group: OS P = 0.018, EFS P = 0.518). Co-occurrence of DNMT3Amut conferred markedly inferior outcomes (No allo-HSCT group: OS P = 0.050, EFS P = 0.011); however, allo-HSCT abrogated this adverse survival impact (allo-HSCT group: OS P = 0.139, EFS P = 0.092), resulting in significant prognostic improvement. Conclusion: Among our AML cohort, pts harboring FLT3-TKDmut exhibited poor overall outcomes, with 5-year OS and EFS rates of 39.6 % and 24.1%, respectively. Achievement of CR after induction, particularly when accompanied by MRD 0.1%, was associated with markedly improved survival. Allo-HSCT conferred significant OS and EFS benefit. Co-occurrence of CBFβ-MYH11mut ameliorated prognosis within the FLT3-TKDmut, whereas concomitant DNMT3Amut portended markedly inferior outcomes; in the latter group, allo-HSCT effectively abrogated the adverse impact.
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