FLT3-mutated acute myeloid leukemia (AML) is characterized by activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor, occurring in approximately 30% of newly diagnosed AML cases. The two main mutation types are internal tandem duplications (ITD) in the juxtamembrane domain (25%) and tyrosine kinase domain (TKD) point mutations (7-10%). FLT3-ITD mutations confer an adverse prognosis with high relapse rates, while FLT3-TKD mutations have intermediate prognostic impact. The development of FLT3 inhibitors (midostaurin, gilteritinib) has significantly improved outcomes for these patients, representing a key example of precision medicine in AML.
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name: Acute Myeloid Leukemia, FLT3-Mutated
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
FLT3-mutated acute myeloid leukemia (AML) is characterized by activating mutations
in the FMS-like tyrosine kinase 3 (FLT3) receptor, occurring in approximately 30%
of newly diagnosed AML cases. The two main mutation types are internal tandem
duplications (ITD) in the juxtamembrane domain (25%) and tyrosine kinase domain
(TKD) point mutations (7-10%). FLT3-ITD mutations confer an adverse prognosis with
high relapse rates, while FLT3-TKD mutations have intermediate prognostic impact.
The development of FLT3 inhibitors (midostaurin, gilteritinib) has significantly
improved outcomes for these patients, representing a key example of precision
medicine in AML.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Molecularly Defined Cancer
parents:
- acute myeloid leukemia
has_subtypes:
- name: FLT3-ITD Mutated AML
description: >-
AML with internal tandem duplications in the juxtamembrane domain of FLT3.
ITD mutations cause ligand-independent receptor dimerization and constitutive
activation. Associated with leukocytosis, high blast percentage, and poor
prognosis, particularly when the ITD allelic ratio is high. Represents the
most clinically significant FLT3 mutation subtype.
- name: FLT3-TKD Mutated AML
description: >-
AML with point mutations in the tyrosine kinase domain of FLT3, most commonly
at codon D835. TKD mutations cause constitutive kinase activation but have a
less adverse prognostic impact than ITD mutations. May co-occur with other
mutations including NPM1.
pathophysiology:
- name: FLT3 Receptor Constitutive Activation
description: >-
FLT3 is a class III receptor tyrosine kinase normally involved in hematopoietic
progenitor cell survival and proliferation. FLT3-ITD mutations cause
ligand-independent receptor dimerization and constitutive autophosphorylation.
FLT3-TKD mutations stabilize the active kinase conformation. Both result in
aberrant downstream signaling.
evidence:
- reference: PMID:41228209
reference_title: "FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML."
supports: SUPPORT
snippet: "In acute myeloid leukemia (AML), FLT3 mutations-most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions-are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis."
explanation: This abstract describes FLT3-ITD/TKD mutations driving constitutive activation in AML, matching the mechanism described.
cell_types:
- preferred_term: myeloblast
term:
id: CL:0000835
label: myeloblast
molecular_functions:
- preferred_term: protein tyrosine kinase activity
modifier: INCREASED
term:
id: GO:0004713
label: protein tyrosine kinase activity
downstream:
- target: STAT5 Hyperactivation
description: Constitutive FLT3 signaling drives STAT5 phosphorylation and nuclear translocation
- target: RAS-MAPK Pathway Activation
description: Activated FLT3 signals through RAS to promote proliferation
- name: STAT5 Hyperactivation
description: >-
FLT3-ITD mutations preferentially activate STAT5 signaling compared to wild-type
FLT3 or TKD mutations. Phosphorylated STAT5 translocates to the nucleus and
activates transcription of anti-apoptotic genes (BCL-XL, PIM1) and cell cycle
regulators, promoting leukemic cell survival and proliferation.
cell_types:
- preferred_term: myeloblast
term:
id: CL:0000835
label: myeloblast
biological_processes:
- preferred_term: signal transduction
modifier: INCREASED
term:
id: GO:0007165
label: signal transduction
downstream:
- target: Apoptosis Resistance
description: STAT5 target genes confer resistance to programmed cell death
- name: RAS-MAPK Pathway Activation
description: >-
FLT3 signaling activates the RAS-RAF-MEK-ERK cascade, driving cell proliferation
and survival. This pathway is critical for the proliferative advantage of
FLT3-mutated leukemic cells.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
downstream:
- target: Uncontrolled Myeloblast Proliferation
description: MAPK signaling promotes cell cycle progression and proliferation
- name: Apoptosis Resistance
description: >-
FLT3-ITD-mediated STAT5 activation upregulates anti-apoptotic proteins including
BCL-XL, MCL-1, and PIM kinases. This confers resistance to apoptosis and
contributes to the aggressive clinical behavior of FLT3-ITD AML.
biological_processes:
- preferred_term: apoptotic process
modifier: DECREASED
term:
id: GO:0006915
label: apoptotic process
- name: Uncontrolled Myeloblast Proliferation
description: >-
The combined effects of enhanced survival signaling and cell cycle promotion
lead to accumulation of immature myeloid blasts in the bone marrow and blood,
replacing normal hematopoiesis.
locations:
- preferred_term: bone marrow
term:
id: UBERON:0002371
label: bone marrow
cell_types:
- preferred_term: myeloblast
term:
id: CL:0000835
label: myeloblast
biological_processes:
- preferred_term: myeloid cell differentiation
modifier: DECREASED
term:
id: GO:0030099
label: myeloid cell differentiation
histopathology:
- name: Myeloblast Predominance
finding_term:
preferred_term: Myeloblasts Present
term:
id: NCIT:C155995
label: Myeloblasts Present
frequency: VERY_FREQUENT
description: Acute myeloid leukemia features increased myeloblasts in blood or marrow.
evidence:
- reference: PMID:23590662
reference_title: "Acute myeloid leukemia: advances in diagnosis and classification."
supports: SUPPORT
snippet: "myeloblasts in the blood or bone marrow."
explanation: Abstract notes myeloblasts in the blood or bone marrow in AML.
phenotypes:
- category: Hematologic
name: Leukocytosis
frequency: VERY_FREQUENT
description: >-
Elevated white blood cell count is particularly common in FLT3-ITD AML,
often exceeding 100,000/uL, reflecting the proliferative nature of the disease.
phenotype_term:
preferred_term: Leukocytosis
term:
id: HP:0001974
label: Increased total leukocyte count
- category: Hematologic
name: Anemia
frequency: VERY_FREQUENT
description: >-
Normocytic normochromic anemia results from bone marrow replacement by
leukemic blasts and ineffective erythropoiesis.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
- category: Hematologic
name: Thrombocytopenia
frequency: VERY_FREQUENT
description: >-
Low platelet count due to bone marrow failure, contributing to
bleeding risk.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
- category: Constitutional
name: Fatigue
frequency: VERY_FREQUENT
description: >-
Profound fatigue related to anemia and hypermetabolic state from
rapid leukemic cell turnover.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Infectious
name: Recurrent Infections
frequency: FREQUENT
description: >-
Increased susceptibility to bacterial and fungal infections due to
neutropenia from bone marrow failure.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
- category: Bleeding
name: Abnormal Bleeding
frequency: FREQUENT
description: >-
Easy bruising, petechiae, mucosal bleeding, and prolonged bleeding
from minor wounds due to thrombocytopenia.
phenotype_term:
preferred_term: Abnormal bleeding
term:
id: HP:0001892
label: Abnormal bleeding
biochemical:
- name: FLT3-ITD Detection
notes: >-
PCR-based assays detect internal tandem duplications in the FLT3
juxtamembrane domain. Allelic ratio (mutant/wild-type) has prognostic
significance, with high ratios indicating worse outcomes.
- name: FLT3-TKD Mutation Analysis
notes: >-
Sequencing or allele-specific PCR detects point mutations at D835 and
other TKD residues. Important for FLT3 inhibitor selection and prognosis.
genetic:
- name: FLT3-ITD
association: Somatic Oncogenic Mutation
notes: >-
Internal tandem duplications in the juxtamembrane domain (exons 14-15)
cause constitutive receptor dimerization and activation. ITD length
and allelic ratio impact prognosis. Co-occurrence with NPM1 mutations
partially mitigates the adverse prognostic impact.
- name: FLT3-TKD
association: Somatic Oncogenic Mutation
notes: >-
Point mutations in the tyrosine kinase domain, most commonly D835Y,
cause constitutive kinase activation. Less adverse prognostic impact
than ITD mutations but still targetable with FLT3 inhibitors.
treatments:
- name: Midostaurin
description: >-
First-generation multi-kinase inhibitor with FLT3 activity approved in
combination with standard chemotherapy (7+3) for newly diagnosed FLT3-mutated
AML. Addition of midostaurin to induction and consolidation significantly
improves overall survival.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: midostaurin
term:
id: CHEBI:63452
label: midostaurin
- name: Gilteritinib
description: >-
Second-generation selective FLT3 inhibitor approved for relapsed/refractory
FLT3-mutated AML. More potent and selective than midostaurin with activity
against both ITD and TKD mutations, including some resistance mutations.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: gilteritinib
term:
id: CHEBI:145372
label: gilteritinib
- name: Intensive Chemotherapy (7+3)
description: >-
Standard induction chemotherapy with cytarabine continuous infusion for
7 days plus anthracycline (daunorubicin or idarubicin) for 3 days. Forms
the backbone of treatment combined with FLT3 inhibitors for eligible patients.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Allogeneic Stem Cell Transplantation
description: >-
Recommended for FLT3-ITD AML patients in first complete remission due to
high relapse risk. Provides graft-versus-leukemia effect. FLT3 inhibitor
maintenance post-transplant is being evaluated.
treatment_term:
preferred_term: hematopoietic stem cell transplantation
term:
id: MAXO:0000747
label: hematopoietic stem cell transplantation
disease_term:
preferred_term: FLT3 mutated acute myeloid leukemia
term:
id: MONDO:0100415
label: acute myeloid leukemia, FLT3 internal tandem duplication
classifications:
icdo_morphology:
classification_value: Leukemia
harrisons_chapter:
- classification_value: cancer
- classification_value: hematologic malignancy
references:
- reference: DOI:10.1002/phar.2039
title: 'Midostaurin: A New Oral Agent Targeting <scp>FMS</scp>‐Like Tyrosine Kinase 3‐Mutant Acute Myeloid Leukemia'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: 'Midostaurin: A New Oral Agent Targeting <scp>FMS</scp>‐Like Tyrosine Kinase 3‐Mutant Acute Myeloid Leukemia'
supporting_text: Acute myeloid leukemia (AML), a clonal hematologic malignancy that results in bone marrow failure, is the most common acute leukemia in adults (median age of diagnosis 67 yrs), and treatment options, especially in the elderly population, are limited.
evidence:
- reference: DOI:10.1002/phar.2039
reference_title: 'Midostaurin: A New Oral Agent Targeting <scp>FMS</scp>‐Like Tyrosine Kinase 3‐Mutant Acute Myeloid Leukemia'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Acute myeloid leukemia (AML), a clonal hematologic malignancy that results in bone marrow failure, is the most common acute leukemia in adults (median age of diagnosis 67 yrs), and treatment options, especially in the elderly population, are limited.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1038/s41375-022-01798-5
title: Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling
supporting_text: Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling
- reference: DOI:10.1038/s41408-023-00911-w
title: 'Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course.
supporting_text: FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course.
evidence:
- reference: DOI:10.1038/s41408-023-00911-w
reference_title: 'Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1038/s41408-024-01143-2
title: Current status and research directions in acute myeloid leukemia
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Current status and research directions in acute myeloid leukemia
supporting_text: Current status and research directions in acute myeloid leukemia
- reference: DOI:10.1056/nejmoa1614359
title: Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a <i>FLT3</i> Mutation
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a <i>FLT3</i> Mutation
supporting_text: Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a <i>FLT3</i> Mutation
- reference: DOI:10.1056/nejmoa1902688
title: Gilteritinib or Chemotherapy for Relapsed or Refractory <i>FLT3</i> -Mutated AML
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Gilteritinib or Chemotherapy for Relapsed or Refractory <i>FLT3</i> -Mutated AML
supporting_text: Gilteritinib or Chemotherapy for Relapsed or Refractory <i>FLT3</i> -Mutated AML
- reference: DOI:10.1158/1078-0432.ccr-20-4271
title: 'FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a <i>FLT3</i> Mutation'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: 'FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a <i>FLT3</i> Mutation'
supporting_text: On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test.
evidence:
- reference: DOI:10.1158/1078-0432.ccr-20-4271
reference_title: 'FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a <i>FLT3</i> Mutation'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1182/blood-2017-05-782292
title: Midostaurin approved for FLT3-mutated AML
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Midostaurin was recently approved by the US Food and Drug Administration for the treatment of FLT3-mutant acute myeloid leukemia (AML).
supporting_text: Midostaurin was recently approved by the US Food and Drug Administration for the treatment of FLT3-mutant acute myeloid leukemia (AML).
evidence:
- reference: DOI:10.1182/blood-2017-05-782292
reference_title: Midostaurin approved for FLT3-mutated AML
supports: SUPPORT
evidence_source: OTHER
snippet: Midostaurin was recently approved by the US Food and Drug Administration for the treatment of FLT3-mutant acute myeloid leukemia (AML).
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1182/blood-2022-162739
title: 'Quantum-First Trial: <i>FLT3</i>-ITD-Specific MRD Clearance Is Associated with Improved Overall Survival'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: 'Quantum-First Trial: <i>FLT3</i>-ITD-Specific MRD Clearance Is Associated with Improved Overall Survival'
supporting_text: 'Quantum-First Trial: <i>FLT3</i>-ITD-Specific MRD Clearance Is Associated with Improved Overall Survival'
- reference: DOI:10.1182/bloodadvances.2021006489
title: Molecular profile of <i>FLT3</i>-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Molecular profile of <i>FLT3</i>-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib
supporting_text: The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML.
evidence:
- reference: DOI:10.1182/bloodadvances.2021006489
reference_title: Molecular profile of <i>FLT3</i>-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1182/bloodadvances.2022007486
title: Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Despite significant advancements in developing selective FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance to treatment is common even on continued therapy.
supporting_text: Despite significant advancements in developing selective FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance to treatment is common even on continued therapy.
evidence:
- reference: DOI:10.1182/bloodadvances.2022007486
reference_title: Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Despite significant advancements in developing selective FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance to treatment is common even on continued therapy.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1182/bloodadvances.2022009010
title: Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection.
supporting_text: Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection.
evidence:
- reference: DOI:10.1182/bloodadvances.2022009010
reference_title: Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1186/s12935-023-03142-y
title: GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation accounts for a large proportion of AML patients and diagnosed with poor prognosis.
supporting_text: Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation accounts for a large proportion of AML patients and diagnosed with poor prognosis.
evidence:
- reference: DOI:10.1186/s12935-023-03142-y
reference_title: GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia
supports: SUPPORT
evidence_source: OTHER
snippet: Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation accounts for a large proportion of AML patients and diagnosed with poor prognosis.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.1186/s13045-024-01617-7
title: 'Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD–positive AML'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: 'Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD–positive AML'
supporting_text: 'Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD–positive AML'
- reference: DOI:10.1186/s40364-024-00649-y
title: 'Global, regional, and national burden of acute myeloid leukemia, 1990–2021: a systematic analysis for the global burden of disease study 2021'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Acute myeloid leukemia (AML), as the most common subtype of leukemia in adults, is characterised by rapid progression and poor prognosis.
supporting_text: Acute myeloid leukemia (AML), as the most common subtype of leukemia in adults, is characterised by rapid progression and poor prognosis.
evidence:
- reference: DOI:10.1186/s40364-024-00649-y
reference_title: 'Global, regional, and national burden of acute myeloid leukemia, 1990–2021: a systematic analysis for the global burden of disease study 2021'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Acute myeloid leukemia (AML), as the most common subtype of leukemia in adults, is characterised by rapid progression and poor prognosis.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.15252/emmm.201910895
title: Follistatin is a novel therapeutic target and biomarker in <scp>FLT</scp> 3/ <scp>ITD</scp> acute myeloid leukemia
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Follistatin is a novel therapeutic target and biomarker in <scp>FLT</scp> 3/ <scp>ITD</scp> acute myeloid leukemia
supporting_text: Follistatin is a novel therapeutic target and biomarker in <scp>FLT</scp> 3/ <scp>ITD</scp> acute myeloid leukemia
- reference: DOI:10.3389/fpubh.2023.1329529
title: 'Global, national, and regional burden of acute myeloid leukemia among 60–89 years-old individuals: insights from a study covering the period 1990 to 2019'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Our study examined the global, national, and regional trends in the incidence, mortality, and disability-adjusted life years (DALYs) associated with older people’s acute myeloid leukemia (AML) over a 30 years period.
supporting_text: Our study examined the global, national, and regional trends in the incidence, mortality, and disability-adjusted life years (DALYs) associated with older people’s acute myeloid leukemia (AML) over a 30 years period.
evidence:
- reference: DOI:10.3389/fpubh.2023.1329529
reference_title: 'Global, national, and regional burden of acute myeloid leukemia among 60–89 years-old individuals: insights from a study covering the period 1990 to 2019'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Our study examined the global, national, and regional trends in the incidence, mortality, and disability-adjusted life years (DALYs) associated with older people’s acute myeloid leukemia (AML) over a 30 years period.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.3390/cancers15082312
title: 'Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: FLT3 mutations are present in 30% of newly diagnosed patients with acute myeloid leukemia.
supporting_text: FLT3 mutations are present in 30% of newly diagnosed patients with acute myeloid leukemia.
evidence:
- reference: DOI:10.3390/cancers15082312
reference_title: 'Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: FLT3 mutations are present in 30% of newly diagnosed patients with acute myeloid leukemia.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.3390/ijms25179448
title: Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML).
supporting_text: FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML).
evidence:
- reference: DOI:10.3390/ijms25179448
reference_title: Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML).
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.3390/jcm12206429
title: A Review of FLT3 Kinase Inhibitors in AML
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood.
supporting_text: Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood.
evidence:
- reference: DOI:10.3390/jcm12206429
reference_title: A Review of FLT3 Kinase Inhibitors in AML
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood.
explanation: Deep research cited this publication as relevant literature for FLT3 Mutant AML.
- reference: DOI:10.7759/cureus.45765
title: 'FLT3 Mutations in Acute Myeloid Leukemia: Unraveling the Molecular Mechanisms and Implications for Targeted Therapies'
found_in:
- FLT3_Mutant_AML-deep-research-falcon.md
findings:
- statement: 'FLT3 Mutations in Acute Myeloid Leukemia: Unraveling the Molecular Mechanisms and Implications for Targeted Therapies'
supporting_text: 'FLT3 Mutations in Acute Myeloid Leukemia: Unraveling the Molecular Mechanisms and Implications for Targeted Therapies'
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the accumulation of immature hematopoietic precursors (blasts) in the bone marrow and peripheral blood. (negotei2023areviewof pages 1-3)
FLT3-mutated AML refers to AML harboring activating mutations in FLT3 (FMS-related receptor tyrosine kinase 3); these mutations occur in ~30% of newly diagnosed AML patients. (fedorov2023targetingflt3mutation pages 1-2)
Key concept—driver alteration: Activating FLT3 mutations are typically somatic lesions that confer proliferative/survival advantages to leukemic clones through constitutive signaling. (fedorov2023targetingflt3mutation pages 1-2)
Commonly used in clinical and research contexts: - “FLT3-mutated AML” / “FLT3+ AML” (short2023treatmentofolder pages 1-2) - “FLT3-ITD AML” (internal tandem duplication) (fedorov2023targetingflt3mutation pages 1-2) - “FLT3-TKD AML” (tyrosine kinase domain point mutation) (fedorov2023targetingflt3mutation pages 1-2)
Most information below is derived from aggregated, disease-level resources (reviews, guidelines, and large registry/GBD studies) and from primary clinical trials (RATIFY, ADMIRAL, QuANTUM-First). (stone2017midostaurinpluschemotherapy pages 1-2, perl2019gilteritiniborchemotherapy pages 1-2, chen2024globalnationaland pages 1-2)
FLT3-mutated AML is driven by activating mutations in FLT3 leading to constitutive receptor signaling (PI3K, STAT5, RAS pathways), increasing leukemic cell survival and proliferation. (fedorov2023targetingflt3mutation pages 1-2)
Recent GBD-based analyses identify major modifiable risk factors associated with AML burden and mortality, including: - Smoking - High body mass index (BMI) - Occupational exposure to benzene and formaldehyde (chen2024globalnationaland pages 1-2, zhou2024globalregionaland pages 13-16)
GBD 2021 global statistics show incident AML cases increased from 79,372 (1990) to 144,645 (2021), while age-standardized incidence rate (ASIR) changed slightly (1.77 to 1.73 per 100,000). (zhou2024globalregionaland pages 2-4)
In older adults (60–89 years), 2019 estimates report 61,559 incident cases, 53,620 deaths, and 990,656 DALYs, and identify smoking, high BMI, and occupational benzene/formaldehyde as significant risk factors for mortality in 2019. (chen2024globalnationaland pages 1-2)
No specific genetic or environmental protective factors for FLT3-mutated AML were identified in the retrieved evidence.
No explicit gene–environment interaction evidence specific to FLT3-mutated AML was retrieved.
Across multiple sources, FLT3-ITD AML is repeatedly associated with higher disease burden and adverse clinical presentation: - Higher leukocyte counts and increased blast percentage at presentation, and higher relapse likelihood. (jalte2023flt3mutationsin pages 3-4) - Higher disease burden and inferior overall and relapse-free survival. (fedorov2023targetingflt3mutation pages 1-2)
General AML symptom cluster (not FLT3-specific but relevant to marrow failure) includes infections, anemia, and bleeding due to impaired normal hematopoiesis. (chen2024globalnationaland pages 1-2)
Frequency data gap: The retrieved sources did not provide robust population-level percentages for individual presenting symptoms (e.g., exact frequency of fever, bruising, etc.) specific to FLT3-mutated AML.
Two main mutation classes: - FLT3-ITD (internal tandem duplications in juxtamembrane domain): ~25% of newly diagnosed AML. (fedorov2023targetingflt3mutation pages 1-2) - FLT3-TKD (point mutations in the activation loop): ~7–10% of newly diagnosed AML. (fedorov2023targetingflt3mutation pages 1-2)
FLT3 mutations are enriched in AML with normal karyotype and are frequently co-mutated with NPM1 and/or DNMT3A. (short2023treatmentofolder pages 1-2)
FLT3 mutations may emerge at relapse; FLT3-ITD arises more commonly at relapse than TKD (8% vs 2%). (fedorov2023targetingflt3mutation pages 1-2)
In up to ~75% of patients with FLT3-ITD at diagnosis, the mutation persists at relapse, often with higher allelic burden. (fedorov2023targetingflt3mutation pages 1-2)
Resistance to FLT3 inhibitors can be: - On-target FLT3 mutations, notably the gatekeeper FLT3 F691L (reported as conferring resistance to all current FLT3 inhibitors in one synthesis). (fedorov2023targetingflt3mutation pages 9-10) - Activation-loop FLT3 mutations (e.g., D835 variants) with class-specific resistance patterns (particularly relevant for type II inhibitors). (smith2022molecularprofileof pages 2-3) - Off-target RAS/MAPK pathway mutations (NRAS, KRAS, PTPN11, CBL, BRAF) emerging under selective pressure. (fedorov2023targetingflt3mutation pages 9-10)
Environmental risk factors are better established for AML overall (not specifically FLT3-mutated AML): smoking, high BMI, and occupational exposures to benzene and formaldehyde contribute to AML-related burden and mortality in GBD analyses. (chen2024globalnationaland pages 1-2, zhou2024globalregionaland pages 13-16)
1) FLT3 activating mutation (ITD/TKD) → 2) Constitutive FLT3 signaling via PI3K, STAT5, and RAS → 3) increased leukemic cell survival/proliferation and impaired differentiation → 4) accumulation of myeloblasts (bone marrow and blood) with suppression of normal hematopoiesis → 5) clinical manifestations (cytopenia-related infections/anemia/bleeding, leukocytosis/blast burden) and higher relapse risk. (fedorov2023targetingflt3mutation pages 1-2, jalte2023flt3mutationsin pages 3-4, chen2024globalnationaland pages 1-2)
A “protective environment within the bone marrow” makes eradication of FLT3-mutant cells difficult and contributes to resistance. (fedorov2023targetingflt3mutation pages 1-2)
Mechanistic studies highlight stromal/niche-derived signals (e.g., CXCL12, FGF2) as mediators of FLT3 inhibitor resistance via MAPK pathway reactivation and leukemia stem cell protection. (fedorov2023targetingflt3mutation pages 9-10, anderson2023microenvironmentalcxcl12deletion pages 10-12)
Extramedullary involvement can occur in AML, including FLT3-mutated subsets, but the retrieved evidence did not provide organ-specific frequencies (e.g., spleen/liver infiltration rates) for FLT3-mutated AML.
AML is an acute leukemia, with incidence increasing with age; ~80% of new AML cases occur in individuals aged ≥60. (chen2024globalnationaland pages 1-2)
FLT3-ITD AML is characterized by high relapse risk after remission and persistence/emergence of FLT3-ITD at relapse in many patients. (fedorov2023targetingflt3mutation pages 1-2)
FLT3 mutations defining FLT3-mutated AML are generally somatic, not inherited in a Mendelian pattern in typical cases (no germline inheritance pattern was supported in the retrieved evidence set).
FLT3 mutation screening at diagnosis is described as mandatory, and WHO is cited as strongly advising FLT3 mutation screening in AML. (negotei2023areviewof pages 1-3)
ELN 2022 removed FLT3-ITD allelic ratio from risk assignment; FLT3-ITD positivity is classified as intermediate risk irrespective of allelic ratio or NPM1 co-mutation (in the absence of adverse cytogenetics/other markers). (lachowiez2023comparisonandvalidation pages 1-2, fedorov2023targetingflt3mutation pages 1-2)
Modern cohorts and validations used integrated cytogenetic and NGS approaches (karyotype, CLIA NGS, WES, fusion testing), and MRD is emphasized as a dynamic marker complementing baseline genetics. (lachowiez2023comparisonandvalidation pages 1-2)
For gilteritinib in relapsed/refractory AML, the FDA approval specifies use in patients with a FLT3 mutation “as detected by an FDA-approved test.” (pulte2021fdaapprovalsummary pages 1-3)
Differential diagnosis details (e.g., AML vs MDS/AML or mixed phenotype acute leukemia) were not systematically extractable from the retrieved evidence set for this report.
Prior to widespread FLT3 inhibitor use, a meta-analysis cited in a 2023 review reported overall survival HR 1.86 and relapse-free survival HR 1.75 for FLT3-ITD (adverse prognosis). (fedorov2023targetingflt3mutation pages 1-2)
Evidence from recent reviews and pivotal trials supports: - Midostaurin + intensive chemotherapy (7+3-based induction and consolidation) for newly diagnosed FLT3-mutated AML. (fedorov2023targetingflt3mutation pages 1-2) - Gilteritinib monotherapy for relapsed/refractory FLT3-mutated AML. (fedorov2023targetingflt3mutation pages 1-2) - Quizartinib + chemotherapy for newly diagnosed FLT3-ITD AML (regulatory status discussed in 2024 reviews). (cortes2024quizartinibapotent pages 1-2, leifheit2024enhancingtherapeuticefficacy pages 6-7)
A concise evidence table is provided below.
| Agent (type I/II; generation) | Setting (newly diagnosed vs R/R; with chemo or mono) | Key trial (name, PMID/DOI, year) | Key efficacy results (OS, CR/CRc, HR where available) | Regulatory notes (FDA approval month/year if explicitly available in evidence) |
|---|---|---|---|---|
| Midostaurin (Type I; 1st generation) | Newly diagnosed FLT3-mutated AML; with intensive chemotherapy (7+3) and consolidation; maintenance studied | RATIFY / CALGB 10603; DOI: 10.1056/NEJMoa1614359; 2017 | Median OS 74.7 vs 25.6 months (fedorov2023targetingflt3mutation pages 2-4, stansfield2017midostaurinanew pages 7-10); OS HR 0.78 (95% CI 0.63-0.96) (stansfield2017midostaurinanew pages 7-10); median EFS 8.2 vs 3.0 months (stansfield2017midostaurinanew pages 7-10); EFS HR 0.78 (95% CI 0.66-0.93) (cortes2024quizartinibapotent pages 1-2, stansfield2017midostaurinanew pages 7-10); CR 58.9% vs 53.5% / ~59% vs 54% (fedorov2023targetingflt3mutation pages 2-4, stansfield2017midostaurinanew pages 7-10) | FDA approved April 2017 for newly diagnosed FLT3-mutated AML (levis2017midostaurinapprovedfor pages 1-6); review notes FDA approval in 2017 (fedorov2023targetingflt3mutation pages 2-4) |
| Gilteritinib (Type I; 2nd generation) | Relapsed/refractory FLT3-mutated AML; monotherapy vs salvage chemotherapy | ADMIRAL; DOI: 10.1056/NEJMoa1902688; 2019 | Median OS 9.3 vs 5.6 months (negotei2023areviewof pages 7-8); HR for death 0.64 (95% CI 0.49-0.83) (negotei2023areviewof pages 7-8); EFS 2.8 vs 0.7 months (negotei2023areviewof pages 7-8); CR/CRh 34.0% vs 15.3% (negotei2023areviewof pages 7-8); CR 21.1% vs 10.5% (from primary trial abstract summarized in evidence search, consistent with ADMIRAL source set) | FDA approved November 28, 2018; label revised May 29, 2019 with final OS analysis (leifheit2024enhancingtherapeuticefficacy pages 6-7) |
| Quizartinib (Type II; 2nd generation) | Newly diagnosed FLT3-ITD+ AML; with induction/consolidation chemotherapy and maintenance | QuANTUM-First; NCT02668653; DOI: 10.1182/blood-2022-162739 (MRD analysis), pivotal phase 3 basis summarized in 2024 review | Median OS 31.9 vs 15.1 months (negotei2023areviewof pages 7-8); delta median OS 16.8 months (levis2022quantumfirsttrialflt3itdspecific pages 1-1); CRc by end of induction 71.6% vs 64.9% (levis2022quantumfirsttrialflt3itdspecific pages 1-1); MRD clearance associated with improved OS (levis2022quantumfirsttrialflt3itdspecific pages 1-1) | FDA approved July 2023 for FLT3-mutated AML patients per review summary; broader 2024 review states approved in US/Japan/Europe/UK for newly diagnosed FLT3-ITD+ AML with chemo and maintenance (leifheit2024enhancingtherapeuticefficacy pages 6-7, cortes2024quizartinibapotent pages 1-2) |
| Quizartinib (Type II; 2nd generation) | Relapsed/refractory FLT3-ITD+ AML; monotherapy | QuANTUM-R; pivotal phase 3, summarized in review; 2024 review context | Median OS 6.2 vs 4.7 months (negotei2023areviewof pages 7-8) | Approved in Japan as monotherapy for adult FLT3-ITD+ R/R AML in 2024 review context (month/year not explicit) (cortes2024quizartinibapotent pages 1-2) |
| Venetoclax + gilteritinib (combination, not yet standard approval as FLT3-labeled regimen) | Relapsed/refractory FLT3-mutated AML; combination oral targeted therapy | Phase Ib/II; DOI: 10.1200/JCO.22.00602; 2022 | mCRc 75% (negotei2023areviewof pages 7-8); median OS 10.0 months (negotei2023areviewof pages 7-8); FLT3 molecular response <10^-2 in 60% of evaluable responders (negotei2023areviewof pages 7-8) | Investigational/combination strategy; no FDA approval month/year stated in evidence (negotei2023areviewof pages 7-8) |
Table: This table summarizes the principal FLT3-targeted therapies used in FLT3-mutated AML, their pivotal trial evidence, and regulatory context. It is useful for quickly comparing frontline versus relapsed/refractory use, efficacy benchmarks, and approval timing.
Gilteritinib labeling includes boxed warning for differentiation syndrome, and warnings for QT prolongation, PRES, pancreatitis, and embryo-fetal toxicity, requiring frequent ECG and chemistry monitoring. (pulte2021fdaapprovalsummary pages 1-3)
Because FLT3-ITD can mediate venetoclax resistance and relapse, combination strategies incorporating FLT3 inhibitors with venetoclax and/or hypomethylating agents are under investigation and show encouraging early results in reviews; mechanistically, FLT3 inhibition can reduce STAT5→MCL-1 signaling that contributes to venetoclax resistance. (short2023treatmentofolder pages 1-2, fedorov2023targetingflt3mutation pages 2-4)
Given poor relapsed/refractory outcomes and high relapse risk in FLT3-ITD AML, allo-HSCT is generally recommended in first complete remission in many treatment paradigms. (fedorov2023targetingflt3mutation pages 1-2)
No primary prevention specific to FLT3-mutated AML was identified; prevention strategies for AML overall focus on modifying population-level risk factors highlighted in GBD analyses: - Tobacco smoking reduction - Obesity/high BMI reduction - Occupational exposure control for benzene and formaldehyde (chen2024globalnationaland pages 1-2, zhou2024globalregionaland pages 13-16)
This section is not directly applicable as a “naturally occurring” transmissible disease; however, AML-like phenotypes driven by FLT3-ITD are modeled in animals (see Model Organisms).
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