Difference between revisions of "Acute Myeloid Leukemia (AML) with Mutated FLT3"

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==Primary Author(s)*==
 
==Primary Author(s)*==
  
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Kay Weng Choy, MBBS, Monash Medical Centre
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__TOC__
 
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==Cancer Category/Type==
 
==Cancer Category/Type==
  
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Acute myeloid leukemia (AML)
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==Cancer Sub-Classification / Subtype==
 
==Cancer Sub-Classification / Subtype==
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==Synonyms / Terminology==
 
==Synonyms / Terminology==
  
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None.
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==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
  
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''FLT3'' mutations occur in about one-third of patients with AML [3]. In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD [3]. The JMD inhibits activation of the receptor by steric hindrance, preventing the TKD from assuming an active conformation; presence of an ITD causes loss of this inhibitory effect, resulting in activation of the TKD.  The second most common type of ''FLT3'' mutations in AML are those within the TKD (occurring in up to 14% of adult patients with AML) [3].
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==Clinical Features==
 
==Clinical Features==
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==Sites of Involvement==
 
==Sites of Involvement==
  
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Bone marrow
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==Morphologic Features==
 
==Morphologic Features==
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==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
  
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None
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==Characteristic Chromosomal Aberrations / Patterns==
 
==Characteristic Chromosomal Aberrations / Patterns==
  
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''FLT3''-ITD and ''FLT3''-TKD mutations are common in patients with AML with normal karyotype but they can also be associated with abnormal karyotype, such as t(15;17)/PML-RARA and core binding factor (''CBF'') AML. ''FLT3''-ITD is frequently associated with t(6;9)(p23;q34.1) abnormalities [12].
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==Genomic Gain/Loss/LOH==
 
==Genomic Gain/Loss/LOH==
  
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None
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==Gene Mutations (SNV/INDEL)==
 
==Gene Mutations (SNV/INDEL)==
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*In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD [3].
 
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*The second most common type of ''FLT3'' mutations in AML are those within the TKD (occurring in up to 14% of adult patients with AML) [3]. The majority are point mutations within the activation loop (e.g., residues D835, I836, Y842) of the TKD2, and within the TKD1 (e.g., residues N676, F691) [3,11]. As a result of amino acid substitutions, changes in the activation loop favor the active kinase conformation.
 
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==Epigenomics (Methylation)==
 
==Epigenomics (Methylation)==
  
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Not applicable.
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==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
  
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''FLT3'' is a member of the type III receptor tyrosine kinase family that regulates hematopoiesis [1]. The receptor is activated by binding of the FLT3 ligand to the extracellular domain, which leads to homodimer formation in the plasma membrane and consequently autophosphorylation of tyrosine residues in the receptor; the activated receptor kinase then phosphorylates and activates multiple cytoplasmic effector molecules involved in proliferation and differentiation of hematopoietic cells in the bone marrow [2]. ''FLT3'' contains five functional domains: an immunoglobulin-like extracellular domain, a transmembrane domain, a juxtamembrane domain (JMD), an interrupted tyrosine kinase domain (TKD), and a small C-terminal domain [3].
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==Diagnostic Testing Methods==
 
==Diagnostic Testing Methods==
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==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
 
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
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*Differences in expression levels [measured using the FLT3-ITD-to-wild-type (WT) allelic ratio] have prognostic implications [3,7,8,9]. It is commonly agreed that a high FLT3-ITD-to-wild-type allelic ratio is a negative prognostic factor (regardless of cytogenetics); the 2017 European Leukemia Net (ELN) guidelines defined 0.5 as the cut-off between low and high allelic ratios [10]. ''FLT3''-ITD remains relevant as a prognostic factor even after intensive chemotherapy and/or stem cell transplant [3]. ''FLT3'' testing was historically viewed as being purely prognostic; however, with the advent of ''FLT3'' inhibitors, it will likely be considered as both prognostic (clinical outcome) and predictive (treatment benefit) [3].
 
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*Allogeneic hematopoietic stem cell transplant (alloHSCT) is generally recommended for patients with ''FLT3''-ITD mutations in first complete remission (CR1), provided they are eligible for transplant therapy and have a suitable donor. Among patients with ''FL3''-ITD mutations in ''CR1'', those who undergo alloHSCT have significantly better outcomes (e.g., prolonged survival and decreased risk of relapse) than those who receive chemotherapy alone. Despite this, ''FLT3''-ITD remains a poor prognostic factor (high relapse rate and short relapse-free and overall survival) after alloHSCT and chemotherapy. Patients with ''FLT3''-ITD AML may benefit from the use of ''FLT3'' tyrosine kinase inhibitors as maintenance therapy to prevent relapse following alloHSCT.
 
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*The prognosis for patients with ''FLT3'' mutations can be affected by the presence or absence of additional mutations. Patients who are ''FLT3''-ITD negative (''FLT3''-ITD-) or ''FLT3''-ITD low and positive for nucleophosmin 1 mutations (NPM1+) have a “favorable” prognosis; patients who are FLT3-ITD- (or FLT3-ITDlow) with NPM1-WT have an intermediate prognosis [10]. On the other hand, patients who are FLT3-ITDhigh with NPM1-WT have a “poor” prognosis and are less likely to achieve complete remission (CR) with induction chemotherapy than patients with other ''FLT3''/''NPM1'' combinations [3,13].
 
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*Given its prognostic and predictive values, it is argued that ''FLT3'' testing should be performed in all AMLs regardless of cytogenetics [3]. If the ''FLT3''-ITD-to-WT allelic ratio is used for risk stratification, harmonisation of ''FLT3'' testing is essential to ensure that comparable results are achieved [3].
 
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*The prognostic significance of ''FLT3''-TKD mutations is controversial and may depend on additional mutations and cytogenetics [3].
 
  
 
==Familial Forms==
 
==Familial Forms==
  
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Not applicable.
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==Other Information==
 
==Other Information==
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==Links==
 
==Links==
  
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[[FLT3]]
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==References==
 
==References==
  
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1. Rosnet O, et al., (1996). Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 10(2):238-248. PMID 8637232.
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2. Liu, S, et al., (2014). MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells. Blood 123(5):734-742. PMID 24282218.
 
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3. Patnaik MM, (2017). The importance of FLT3 mutational analysis in acute myeloid leukemia. Leuk Lymphoma 22:1-14. PMID 29164965.
 
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4. Kayser S, et al., (2009). Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 114(12):2386-2392. PMID 19602710.
 
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5. Papaemmanuil E, et al, (2016). Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374:2209-2221. PMID 27276561.
 
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6. Patel JP, et al., (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366(12):1079-1089. PMID 22417203.
 
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7. Thiede C, et al., (2002). Analysis of FLT3- activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99(12):4326-4335. PMID 12036858.
 
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8. Pratcorona M, et al, (2002). Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood 121:2734-2738. PMID 23377436.
 
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9. Gale RE, et al., (2008). The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111(5):2776-2784. PMID 17957027.
 
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10. Dohner H, et al., (2017). Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424-447. PMID 27895058.
 
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11. Smith CC, et al., (2012). Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485:260-263. PMID 22504184.
 
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12. Oyarzo MP, et al., (2004). Acute myeloid leukemia with t(6;9) (p23;q34) is associated with dysplasia and a high frequency of flt3 gene mutations. Am J Clin Pathol 122(3):348-358. PMID 15362364.
 
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13. Walter RB, et al., (2015). Resistance prediction in AML: analysis of 4601 patients from MRC/ NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center. Leukemia 29(2):312-320. PMID 255113226.
 
  
 
==Notes==
 
==Notes==

Revision as of 17:52, 5 January 2019

Primary Author(s)*

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Cancer Category/Type

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Cancer Sub-Classification / Subtype

Put your text here

Definition / Description of Disease

Put your text here

Synonyms / Terminology

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Epidemiology / Prevalence

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Clinical Features

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Sites of Involvement

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Morphologic Features

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Immunophenotype

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Finding Marker
Positive (universal) EXAMPLE CD1
Positive (subset) EXAMPLE CD2
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

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Characteristic Chromosomal Aberrations / Patterns

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Genomic Gain/Loss/LOH

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Gene Mutations (SNV/INDEL)

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Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
EXAMPLE TP53 EXAMPLE R273H EXAMPLE Tumor Suppressor EXAMPLE LOF EXAMPLE 20%

Other Mutations

Type Gene/Region/Other
Concomitant Mutations EXAMPLE IDH1 R123H
Secondary Mutations EXAMPLE Trisomy 7
Mutually Exclusive EXAMPLE EGFR Amplification

Epigenomics (Methylation)

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Genes and Main Pathways Involved

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Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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Familial Forms

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Other Information

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Links

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References

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Notes

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