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Leukemia - Acute

Recurrent genetic abnormalities

AML with FLT3 mutations


Reviewer: Daniela Mihova, M.D. (see Reviewers page)
Revised: 17 February 2013, last major update September 2012
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

General
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● Not a WHO diagnosis
● Mutations of FMS-related tyrosine kinase 3 (FLT3, gene located on 13q12) occur in all types of AML and MDS (Atlas of Genetics and Cytogenetics)
● Most frequent molecular abnormality in AML (20-40% of cases)
● AML: mutations occur most often in t(6;9)(p23;q34), APL t(15;17), AML with normal karyotype
● Usually peripheral leukocytosis and normal cytogenetics
CD135 is receptor for FLT3 ligand / FLT3L

Prognostic factors
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● Mutations include internal tandem duplication within juxtamembrane domain (ITD, 75-80%) and tyrosine kinase domain (TKD) in codon 836 (20-35%)
● FLT3-ITD: poor prognosis (Blood 2002;100:1532)
● FLT3-ITD with NPM1, t(15;17), t(8;21), inv(16) and t(16;16): worse prognosis
● FLT3-ITD with CEBPA: unclear prognosis
● FLT3-TKD: doesn’t affect prognosis (Blood 2008;111:2527)

Diagrams
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FLT3 structure      Molecular heterogeneity of cytogenetically normal AML

Treatment
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● C220 and midostaurin are in phase II clinical trials for AML patients with FLT3 mutations (Clinical Trials)
● Sorafenib may show significant activity (Blood 2009;113:6567, J Natl Cancer Inst 2008;100:184)

Micro description
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● Monocytic differentiation
● Usually AML M2, M4, M5b (Blood 2008;111:2527)

Molecular description
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● Usually normal cytogenetics
● Most common mutation is internal tandem duplication mutation (ITD)
● Cooperating mutations with NPM1, CEBPA and MLL-PTD

Molecular images
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Activating ITD mutations

End of Leukemia - Acute > Recurrent genetic abnormalities > AML with FLT3 mutations


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