Changes

==Primary Author(s)*==

==Primary Author(s)*==

Dr Kay Weng Choy MBBS, BMedSci, FAACB, Monash Health

Kay Weng Choy, MBBS, Monash Medical Centre

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==Synonyms / Terminology==

==Synonyms / Terminology==

==Epidemiology / Prevalence==

==Epidemiology / Prevalence==

==Sites of Involvement==

==Sites of Involvement==

==Morphologic Features==

==Morphologic Features==

{| class="wikitable sortable"

{| class="wikitable sortable"

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! Finding   !! Marker

!Finding!!Marker

|-

|-

|Positive (universal) || EXAMPLE CD1

|Positive (universal)||EXAMPLE CD1

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|Positive (subset) || EXAMPLE CD2

|Positive (subset)||EXAMPLE CD2

|-

|-

|Negative (universal) || EXAMPLE CD3

|Negative (universal)||EXAMPLE CD3

|-

|-

|Negative (subset) || EXAMPLE CD4

|Negative (subset)||EXAMPLE CD4

|}

|}

==Gene Mutations (SNV/INDEL)==

==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].

*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 confirmation. The prognostic significance of ''FLT3''-TKD mutations is controversial and may depend on additional mutations and cytogenetics [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.

{| class="wikitable sortable"

{| class="wikitable sortable"

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! Gene !! Mutation !! Oncogene/Tumor Suppressor/Other !! Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) !! Prevalence (COSMIC/TCGA/Other)

!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)

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| EXAMPLE TP53 || EXAMPLE R273H || EXAMPLE Tumor Suppressor || EXAMPLE LOF || EXAMPLE 20%

|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%

|}

|}

{| class="wikitable sortable"

{| class="wikitable sortable"

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! Type !! Gene/Region/Other

!Type!!Gene/Region/Other

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| Concomitant Mutations || EXAMPLE IDH1 R123H

|Concomitant Mutations||EXAMPLE IDH1 R123H

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| Secondary Mutations || EXAMPLE Trisomy 7

|Secondary Mutations||EXAMPLE Trisomy 7

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|Mutually Exclusive || EXAMPLE EGFR Amplification

|Mutually Exclusive||EXAMPLE EGFR Amplification

|}

|}

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

==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].

*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.

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].

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].

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==

==Familial Forms==

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.

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==

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.