Acute Myeloid Leukemia (AML) with Mutated FLT3

Primary Author(s)*

Kay Weng Choy, BMedSci MBBS FAACB Monash Health

Cancer Category/Type

Acute myeloid leukemia (AML)

Cancer Sub-Classification / Subtype

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Definition / Description of Disease

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Synonyms / Terminology

None.

Epidemiology / Prevalence

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].

Clinical Features

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Sites of Involvement

Bone marrow

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)

None

Characteristic Chromosomal Aberrations / Patterns

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].

Genomic Gain/Loss/LOH

None

Gene Mutations (SNV/INDEL)

• 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 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.

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)

Not applicable.

Genes and Main Pathways Involved

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].

Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

• 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].

• 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.

• 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].

• 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].

• The prognostic significance of FLT3-TKD mutations is controversial and may depend on additional mutations and cytogenetics [3].

Familial Forms

Not applicable.

Other Information

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Links

FLT3

References

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.

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.

3. Patnaik MM, (2017). The importance of FLT3 mutational analysis in acute myeloid leukemia. Leuk Lymphoma 22:1-14. PMID 29164965.

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.

5. Papaemmanuil E, et al, (2016). Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374:2209-2221. PMID 27276561.

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.

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.

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.

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.

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.

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.

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.

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

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