Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Other AML of clinical relevance
AML with FLT3

Editorial Board Member: Patricia Tsang, M.D., M.B.A.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Etan Marks, D.O.

Minor changes: 20 July 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: AML[TI] FLT3[TI] free full text[SB]

Etan Marks, D.O.
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Cite this page: Marks E. AML with FLT3. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/bonemarrowneoplasticAMLFLT3.html. Accessed August 13th, 2020.
Definition / general
  • Not a specific WHO designated entity but has specific prognostic and treatment ramifications
  • FLT3 (FMS-like tyrosine kinase 3) gene encodes a membrane bound receptor tyrosine kinase and is located on chromosome 13q12
  • 2 mutation types in leukemia: internal tandem duplication (ITD), usually within the juxtamembrane domain, and a missense point mutation on the tyrosine kinase domain (TKD)
Essential features
  • Can be found in ~30% of cytogenetically normal acute myeloid leukemia (AML) (Br J Haematol 2017;179:530)
  • Up to 40% of acute promyelocytic leukemia (APL) patients have FLT3 mutations
  • ~20% of AML cases with t(9;11)(p21.3;q23.3) have point mutations in FLT3
  • High percentage (~70%) of AML with t(6;9)(p23;q34.1) have FLT3 mutations (Leukemia 2006;20:1295)
  • Higher prevalence in younger patients with AML (< 60 years old) (Ann Hematol 2017;96:1993)
  • There are several new FLT3 targeted drugs that show promising results, which necessitate rapid analysis of the¬†FLT3¬†status in patients with AML
Terminology
  • FMS-like tyrosine kinase 3
ICD coding
  • ICD-10: C92.00 - Acute myeloblastic leukemia, not having achieved remission
  • ICD-10: C92.01 - Acute myeloblastic leukemia, in remission
  • ICD-10: C92.02 - Acute myeloblastic leukemia, in relapse
Epidemiology
Clinical features
Diagnosis
  • FLT3 mutations are generally detected in the clinical laboratory by PCR and electrophoresis based product sizing as well as using next generation sequencing (NGS) platforms
Prognostic factors
  • FLT3-ITD is an independent adverse prognostic indicator in AML
  • Favorable outcome if mutated nucleophosmin (NPM1) without FLT3-ITD or with FLT3-ITDlow (allelic ratio < 0.5)
  • Intermediate outcome if mutated NPM1 and FLT3-ITDhigh (allelic ratio ≥ 0.5) or wild type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse risk genetic lesions)
  • Adverse outcome if wild type NPM1 and FLT3-ITDhigh
  • Prognostic impact of FLT3-TKD mutations is uncertain (Leukemia 2019;33:299)
  • Acute promyelocytic leukemia with FLT3 mutations appear to represent a subset of APL patients who have a higher risk of relapse (Am J Hematol 2010;85:956)
Case reports
Treatment
Microscopic (histologic) description
  • No specific microscopic findings associated with FLT3 mutation
  • No correlation with a single, specific French-American-British (FAB) subtype was found (Blood 2002;100:59)
  • When FLT3 occurs with other mutations or cytogenetic abnormalities, the characteristic microscopic features seen with those abnormalities are usually present
Microscopic (histologic) images

Contributed by Etan Marks, D.O.

Bone marrow core biopsy

CD34 bone marrow

Virtual slides

Images hosted on other servers:

Peripheral smear of AML

Peripheral smear description
  • Similar to other acute myeloid leukemias with ≥ 20% myeloblasts or ≥ 20% promyelocytes
Peripheral smear images

Contributed by Etan Marks, D.O.

Large irregular myeloblasts

Back to back myeloblasts

Positive stains
Molecular / cytogenetics description
  • FLT3-ITD mutations consist of a duplicated coding sequence usually derived from the juxtamembrane domain inserted in tandem (ITD) (Haematologica 2011;96:1470, Cytometry B Clin Cytom 2013;84:390)
    • These in frame insertion mutations range from 3 to > 200 bp in length and result in disruption of the autoinhibitory function
  • FLT3-TKD point mutations occur in the activation loop of the kinase domain, most commonly at residue aspartate 835 (D835)
Sample pathology report
  • FLT3 is usually reported as an addendum following the initial diagnosis of AML
Differential diagnosis
Board review style question #1
Which mutational combination carries with it the worst overall prognosis in AML?

  1. 5q deleted AML
  2. Mutated FLT3 and wild type NPM1
  3. Wild type FLT3 and mutated NPM1
  4. Wild type NPM1 and biallelic mutated CEBPA
Board review answer #1
B. Mutated FLT3 and wild type NPM1

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Reference: AML with FLT3
Board review style question #2

Which AML with cytogenetic abnormalities has the highest frequency of FLT3 mutations?

  1. Acute promyelocytic leukemia
  2. AML with 5q deletion
  3. AML with t(6;9)(p23;q34.1)
  4. AML with t(9;11)(p21.3;q23.3)
Board review answer #2
C. AML with t(6;9)(p23;q34.1)

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Reference: AML with FLT3
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