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FLT3 Mutation

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed on hematopoietic progenitor cells and plays a crucial role in hematopoiesis. FLT3 mutations lead to constitutive activation of the FLT3 receptorThere are 2 major classes of FLT3-activating mutations:

  • Internal tandem duplications (ITDs) in the juxtamembrane domain of the tyrosine kinase
  • Point mutations in the tyrosine kinase domain (TKD), typically in the D835 residue

FLT3-ITD mutation is found in approximately 25% of patients with cytogenetically normal acute myeloid leukemia (AML). FLT3-ITD mutation is associated with worse outcomes due to higher risk of relapse. FLT3 point mutations are found in 5% of cytogenetically normal cases of AML. Their prognostic significant is not known.

FLT3 mutation can occur with other mutations such as DNA (cytosine 5)-methyltransferase 3A (DNMT3A) and nucleophosmin-1 (NPM1) mutations. FLT3mutations are typically considered late events in leukemogenesis, whereas DNMT3A and NPM1mutations occur relatively early.

College of American Pathologist and American Society of Hematology guidelines for acute leukemia strongly recommend FLT3 mutation analysis at the time of diagnosis. The polymerase chain reaction (PCR) assay for FLT3-ITD mutations amplifies exon 14 or exon 15, which typically contain the ITDs.

The FLT3mutant allele can be quantified in 2 ways:

  • The variant allelic frequency compares the amount of ITDs to the sum of the mutated and wild-type (WT) forms of the FLT3segment
  • The allelic ratio is the ratio of ITDs to WT forms

The FLT3-ITD mutation allelic ratio appears to be prognostically important, but has not been standardized for clinical decision making.

Nextgen sequencing detects a broader array of mutations, but may miss FLT3 ITD. For this reason, PCR is recommended. 

Rapid identification of FLT3 mutations is critical to determine the best therapy and optimize outcomes. FLT3inhibitors are generally classified as first- or second-generation agents. The second-generation inhibitors are more potent and more specific for FLT3relative to the first-generation inhibitors. Midostaurin has been approved by FDA for treatment of patients with FLT3 mutations. Addition of midostaurin to standard AML therapy has improved the survival of young adults with AML and FLT3 mutations.

Arber DA et al. Arch pathol lab med. 2017;141:1342-93 

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