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Symposium | FLT3 mutations in AML: Types, prevalence, and clinical significance
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Jorge SierraDo you know... How is newly diagnosed FLT3-ITD AML classified by the European Leukemia Network?
The AML Hub held a virtual symposium on November 19, 2025, titled, “Understanding the differences between FLT3-ITD and -TKD mutations in AML: Implications for clinical practice.” Here, we share a presentation by Jorge Sierra, Hospital de la Santa Creu i Sant Pau, Barcelona, ES, discussing the types, prevalence, and clinical significance of FLT3 mutations in acute myeloid leukemia (AML).
Symposium | FLT3 mutations in AML: Types, prevalence, and clinical significance
Symposium | FLT3 mutations in AML: Types, prevalence, and clinical significance
Sierra provided an overview of the role of FLT3-internal tandem duplication (ITD) and -tyrosine kinase domain (TKD) mutations in AML pathogenesis, and the differences in their molecular characteristics. He then discussed the prognostic value of FLT3-ITD and -TKD and concomitant mutations in patients with AML, and current risk stratification guidelines.
Key points
- Approximately one-third of patients with AML have FLT3-ITD or -TKD mutations.1–3
- FLT3-internal tandem duplications (ITD) in the juxtamembrane domain are present in 20–25% of AML cases,4 while mutations in the FLT3-tyrosine kinase domain occur in 7–10% of patients with AML (Figure 1).2,3
- FLT3 mutations result in constitutive activation of the FLT3 receptor and downstream pathways, leading to increased proliferation of leukemic cells.5
Figure 1. FLT3 signaling5
- FLT3 mutations are the most common type of genetic mutation in patients aged up to 65 years old and the seventh most prevalent in patients aged more than 65 years old.6,7
- The AMLSG BiO study confirmed that the prevalence of FLT3 mutations decreases with increasing age, with the highest rate (23%) in patients aged 45 years or younger.8
- It is important to assess the presence of concomitant mutations in patients with FLT3-mutated (FLT3m) AML, due to the potential prognostic impact.
- NPM1, DNMT3A, WT1, and CEBPA are the most commonly co-mutated genes in FLT3m AML.2
- A lower probability of survival has been demonstrated in patients with FLT3-ITD AML with NPM1 or DNMT3A co-mutations, vs those without FLT3-ITD (p = 0.009).6
- The prognostic value of FLT3-ITD measurable residual disease (MRD) has also been reported; the presence of FLT3-ITD MRD was associated with increased relapse incidence and reduced overall survival (OS) following two courses of induction chemotherapy in HOVON and CIBMTR studies,9,10 and prior to hematopoietic stem cell transplantation (HSCT) in an AMLSG study.11
- For patients fit for intensive therapy, the European Leukemia Network (ELN) 2022 risk classification defines FLT3-ITD at initial diagnosis as intermediate risk, regardless of NPM1 mutation status.12
- For patients receiving less intensive therapy, the ELN 2024 risk classification also defines FLT3-ITD as intermediate risk.13
- A meta-analysis revealed that the presence of FLT3-TKD alone does not have prognostic impact;14 however, the co-occurrence of FLT3-ITD and CBF or NPM1 mutations has been associated with favorable prognosis.15,16
- Re-evaluation of FLT3 mutation status at relapse is important; changes in FLT3 mutation status between diagnosis and relapse occur in 0.8–30.4% of patients with AML.17-25
- FLT3-ITD has also been identified as a prognostic factor in relapsed/refractory AML (Figure 2).26
- Using data from the HOVON-SAKK studies, a revised prognostic model has been developed which integrates FLT3-ITD as a prognostic marker; this updated model provides OS risk stratification for patients in first relapse and may help guide second-line treatment decisions.27
Figure 2. FLT3-ITD as a prognostic factor in relapsed/refractory AML26
This educational resource is independently supported by Daiichi Sankyo. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.
References
Fröhling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: A study of the AML Study Group Ulm. Blood. 2002;100(13):4372-4380. DOI: 10.1182/blood-2002-05-1440
Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089. DOI: 10.1056/NEJMoa1112304
Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909-1918. DOI: 10.1056/NEJMoa074306
Weisberg E, Barrett R, Liu Q, et al. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist Updat. 2009;12(3):81-89. DOI: 10.1016/j.drup.2009.04.001
Knight TE, Edwards H, Meshinchi S, et al. "FLipping" the Story: FLT3-mutated acute myeloid leukemia and the evolving role of FLT3 inhibitors. Cancers. 2022;14(14):3398. DOI: 10.3390/cancers14143398
Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209-2221. DOI: 10.1056/NEJMoa1516192
Döhner H, Dolnik A, Tang L, et al. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care. Leukemia. 2018;32:2546-2557. DOI: 10.1038/s41375-018-0257-z
Nagel G, Weber D, Fromm E, et al. Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol. 2017;96:1993-2003. DOI: 10.1007/s00277-017-3150-3
Grob T, Sanders MA, Vonk CM, et al. Prognostic value of FLT3-internal tandem duplication residual disease in acute myeloid leukemia. J Clin Oncol. 2022;41:756-765. DOI: 10.1200/JCO.22.00715
Dillon LW, Gui G, Page KM, et al. DNA sequencing to detect residual disease in adults with acute myeloid leukemia prior to hematopoietic cell transplant. JAMA. 2023;329(9):745-755. DOI: 10.1001/jama.2023.1363
Rücker FG, Bullinger L, Cocciardi S, et al. Measurable residual disease monitoring in AML with FLT3-ITD treated with intensive chemotherapy plus midostaurin. Blood Adv. 2024;8(23):6067-6080. DOI: 10.1182/bloodadvances.2024013758
Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377. DOI: 10.1182/blood.2022016867
Döhner H, DiNardo CD, Appelbaum FR, et al. Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations. Blood. 2024;144(21):2169-2173. DOI: 10.1182/blood.2024025409
Li S, Li N, Chen Y, et al.FLT3-TKD in the prognosis of patients with acute myeloid leukemia: A meta-analysis. Front Oncol. 2023;13:1086846. DOI: 10.3389/fonc.2023.1086846
Boddu P, Kantarjian H, Borthakur G, et al. Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Adv. 2017;1(19):1546-1550. DOI: 10.1182/bloodadvances.2017009019
Voso MT, Larson RA, Jones D, et al. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: A subanalysis from the RATIFY trial. Blood Adv. 2020;4(19):4945-4954. DOI: 10.1182/bloodadvances.2020002904
Schnittger S, Kern W, Tschulik C, et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood. 2009;114:2220-2231. DOI: 10.1182/blood-2009-03-213389
Warren M, Luthra R, Yin CC, et al. Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol. 2012;25:1405-1412. DOI: 10.1038/modpathol.2012.88
Schnittger S, Schoch C, Kern W, et al. FLT3 length mutations as marker for follow-up studies in acute myeloid leukaemia. Acta Haematologica. 2004;112:68-78. DOI: 10.1159/000077561
Shih L, Huang C, Wu J, et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: A comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood. 2002;100:2387-2392. DOI: 10.1182/blood-2002-01-0195
McCormick S, McCormick MJ, Grutkoski PS, et al. FLT3 mutations at diagnosis and relapse in acute myeloid leukemia: Cytogenetic and pathologic correlations, including cuplike blast morphology. Arch Pathol Lab Med. 2010;134:1143-1151. DOI: 10.5858/2009-0292-OA.1
Kottaridis PD, Gale RE, Langabeer SE, et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: Implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100:2393-2398. DOI: 10.1182/blood-2002-02-0420
Palmisano M, Grafone T, Ottaviani E, et al. NPM1 mutations are more stable than FLT3 mutations during the course of disease in patients with acute myeloid leukemia. Haematologica. 2007;92:1268-1269. DOI: 10.3324/haematol.11202
Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20(7):1217‐1220. DOI: 10.1038/sj.leu.2404246
National Comprehensive Cancer Network® (NCCN®). Acute Myeloid Leukemia (Version 2.2026). Accessed Oct 2025.
Montesinos P, Bergua J, Infante J, et al. Update on management and progress of novel therapeutics for R/R AML: An Iberian expert panel consensus. Ann Hematol. 2019;98:2467-2483. DOI: 10.1007/s00277-019-03820-w
van der Maas NG, Breems D, Klerk CPW, et al. A revised prognostic model for patients with acute myeloid leukemia and first relapse. Blood Adv. 2025;9(15):3853-3864. DOI: 10.1182/bloodadvances.2025015797
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