Some AML mutations are
more aggressive than others1,2

Learn more about several
key mutations below.

Consider mutation status in your
treatment strategy

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a high degree of recurrent genetic mutations, several of which have been linked to poor prognosis.1,9 These mutations include:

FLT3-ITD11-14

Prevalence:
25%

ASXL117,18

Prevalence:
7% to 11%

RUNX120,21

Prevalence:
10%

TP5320,23,24

Prevalence:
3% to 8%

KIT20,27

Prevalence:
4%

Among the most common of these is FLT3-ITD, one of the two major classes of activating mutations that can occur within FLT3.1,9,48,49

FLT3 is mutated in ≈1/3 of newly diagnosed AML cases, the majority of which are cytogenetically normal AML (CN-AML).1,14,45,50-52 While FLT3 mutations can occur as either internal tandem duplications (ITDs) or point mutations in the tyrosine kinase domain (TKD), ITD mutations are more prevalent.1,45 Additionally, only ITD mutations have been linked definitively to poor prognosis.1,45 Although some studies show an association between FLT3-TKD mutations and poor prognosis, others show no prognostic impact or favorable outcomes associated with FLT3-TKD mutations.1,45

FLT3-ITD

Prevalence: 25%11-14
Prognostic impact: poor1,15,16

FLT3-TKD

Prevalence: 7%1,45
Prognostic impact: undetermined1,45

AML, acute myeloid leukemia; CN-AML, cytogenetically normal AML; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication; FLT3-TKD, FLT3 tyrosine kinase domain; FLT3 WT, FLT3 wild type; ITD, internal tandem duplication; TKD, tyrosine kinase domain.
FLT3-ITD mutation: one of the worst
molecular prognostic factors in AML1,16

The FLT3-ITD mutation constitutively activates FLT3 kinase activity, inhibits cell differentiation, and drives proliferation and survival of leukemic cells.16 Patients with AML harboring a FLT3-ITD mutation typically have a significant disease burden presenting as leukocytosis, with high infiltration of bone marrow.50

The FLT3-ITD mutation in AML has been

associated with significantly shorter51-56,a:

Overall survival
(OS)

 

Remission duration

 

Disease- or event-free survival

 
a Compared with FLT3 wild type.

 

The FLT3-ITD mutation continues to be aggressive in R/R AML57,58

Following induction chemotherapy, clonal evolution may result in changes in FLT3-ITD mutational status in patients with relapsed or refractory (R/R) disease.57-59 In one study, gains of the mutation occurred 6 times more frequently than losses.58

As FLT3-mutated AML evolves from diagnosis to relapse, allelic burden also may evolve and may lead to a higher mutant allelic ratio.50

Median survival from relapse for patients with FLT3-ITD—mutated or FLT3 WT AML60,a

FLT3-ITD—mutated AML

13 weeks

FLT3 WT AML

37 weeks

a As reported in a single-center study of patients with normal karyotype AML whose FLT3 status was determined at diagnosis. Data is reported from a subset of 127 relapsed patients.

 

In patients with relapsed AML, the presence of the FLT3-ITD mutation is associated with significantly worse OS compared with FLT3-ITD—negative disease,60,61 as well as shorter duration of second remission (CR2) following salvage therapy.60

In a subset of patients with FLT3-ITD—mutations and shorter first remissions (<6 months) who were treated with salvage chemotherapy in one study, reported response rates and OS were particularly low.62

AML, acute myeloid leukemia; CR2, second remission; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication; FLT3 WT, FLT3 wild type; OS, overall survival; R/R, relapsed or refractory.
Patients with FLT3-ITD mutations may benefit from HSCT63-65

In newly diagnosed patients with FLT3-ITD–mutated AML, hematopoietic stem cell transplantation (HSCT) has been associated with longer OS, compared to patients who either did not complete HSCT or received chemotherapy.63-65

HSCT may also offer potential for long-term survival in some patients with R/R AML.66,67

Share your experience
Of your newly diagnosed or R/R patients with AML, what percentage do you believe have a FLT3-ITD mutation?
Fewer than 25%
25%-49%
50%-74%
75%-100%

See how others responded:
Reported Percentage of patients with AML who have a FLT-ITD mutation, either at diagnosis or at relapse

GENETIC LANDSCAPE
AML is a heterogeneous disease1,9

In addition to FLT3 mutations, acute myeloid leukemia (AML) may be characterized by other recurrent cytogenetic and genetic alterations, including9,45,48,68:

Other mutations

Amplifications

Deletions

Rearrangements

Some mutations tend to accumulate in a nonrandom order, either occurring early or being acquired late in the process of normal hematopoietic stem cells or progenitor cells transforming to leukemia.69,70

Research suggests that AML genomes contain numerous genetic mutations, with at least 1 founder mutation triggering the disease and other cooperating mutations occurring at relapse.20,69,70

Consider mutational status when1,2,45:
  • subclassifying AML
  • predicting prognosis
  • determining treatment strategies

each mutation in the table below to learn more about it.

Prevalence and prognostic impact of key AML mutations
Mutation
Prevalence
Prognostic impact
FLT3-ITD is one of the worst molecular prognostic factors in AML1,15,16

FLT3 is a ligand-activated receptor tyrosine kinase that is normally expressed by hematopoietic stem/progenitor cells and has important roles in early stages of both myeloid and lymphoid lineage development.16,71,72

Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of newly diagnosed AML cases.1,45,50,51 Compared with FLT3 wild type, FLT3-ITD has been associated with significantly shorter OS, remission duration, and disease- or event-free survival.51-56

AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication; OS, overall survival.
ASXL1 mutations generally carry a poor prognosis18,19

The ASXL1 protein is believed to play a role in epigenetic regulation.43,73 Mutations of ASXL1 have been reported in about 7% to 11% of de novo AML cases, with greater incidence in patients 60 years of age.17,18,73 These mutations have been associated with unfavorable clinical outcomes, including shortened OS, especially in patients with RUNX1 co-mutations.18,19

AML, acute myeloid leukemia; ASXL1, additional sex combs–like 1; OS, overall survival; RUNX1, runt related transcription factor 1.
Mutated RUNX1 confers a poor prognosis in de novo AML21,22

Transcription factor RUNX1 plays a key role in hematopoietic stem cell emergence and regulation.74-76 It is genetically altered in approximately 10% of de novo AML cases through chromosomal translocations or point mutations.20,21

RUNX1 mutations are associated with fewer responses to induction chemotherapy and shortened OS in patients with AML.21,77 This is in contrast to some identified gene fusions involving RUNX1, such as RUNX1-RUNX1T1, which have been shown to have a favorable prognostic impact.78

AML, acute myeloid leukemia; OS, overall survival; RUNX1, runt related transcription factor 1; RUNX1T1, RUNX1 translocation partner 1.
TP53 mutations confer an aggressive disease course and chemotherapy resistance25,26

The TP53 tumor suppressor gene has a variety of antitumor functions—including an ability to modulate apoptosis, autophagy, cell cycle arrest, and cellular senescence—and can be suppressed by mutations as well as through negative regulation by MDM2.79-81 Mutations of TP53 occur in approximately 3% to 8% of AML cases at diagnosis and are commonly associated with complex karyotype AML.20,23,82

AML, acute myeloid leukemia; TP53, tumor protein p53.
KIT mutations may adversely affect clinical outcomes in core binding factor AML (CBF AML)1,28

KIT is a tyrosine kinase receptor believed to be heavily involved in normal hematopoiesis.27 The KIT gene has rare mutations in AML; reported incidences are approximately 4%, with higher rates in patients with AML who have core binding factor mutations, as in CBF AML.20,27

In patients with CBF AML, particularly those with t(8;21), KIT mutations are associated with a higher risk of relapse, decreased remission duration, and adversely affected OS.1,28

AML, acute myeloid leukemia; CBF AML, core binding factor AML; OS, overall survival.
NPM1 mutations are considered driver mutations in AML pathogenesis83

The NPM1 gene has been implicated in ribosome biogenesis and transport, centrosome duplication, and chromatin remodeling, among other cellular events.84-86

Mutations of NPM1 are thought to trigger proliferation and leukemogenesis in myeloid cells; they are present in approximately 28% to 35% of AML cases and about 50% of CN-AML cases.1,20,29,87,88

NPM1 mutations are prognostically favorable in the absence of FLT3-ITD mutations30-32

Clinical outcomes for patients with NPM1 mutations are largely dependent on other co-mutations.89 Without concomitant FLT3-ITD mutations, NPM1 mutations are associated with enhanced therapeutic response to induction therapy and, for patients with CN-AML, improved outcomes.30-32

AML, acute myeloid leukemia; CN-AML, cytogenetically normal AML; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; NPM1, nucleophosmin 1.
Double mutations of CEBPA are associated with favorable survival in AML33,34

CEBPA is a transcription factor thought to be critical to gene expression in hematopoiesis, acting as a differentiation regulator.90 Genetic alterations of CEBPA occur in about 5% to 14% of de novo AML cases as either single or double mutations, often involving a combination of an N-terminal and a bZIP gene mutation.20,33 Biallelic mutated CEBPA is considered a favorable prognostic factor.1,2

AML, acute myeloid leukemia; CEBPA, CCAAT enhancer binding protein alpha.
DNMT3A mutations may be a factor in AML prognosis35,36,91

The DNMT3A enzyme is an epigenetic modifier and a catalyst for DNA methylation, involved in establishing the patterns of DNA methylation early in embryogenesis.92 Mutations of DNMT3A are considered preleukemic, emerging early on and persisting even during remission.93 They have been reported in about 20% of de novo AML cases, with a higher incidence in CN-AML cases.20,94

While some studies demonstrated shorter survival in patients with AML who have mutated DNMT3A, others have not consistently shown it to affect prognosis.35,36,91,94

AML, acute myeloid leukemia; CN-AML, cytogenetically normal AML; DNMT3A, DNA methyltransferase 3 alpha.
The prognostic impact of IDH mutations in AML is not well defined38-40

The IDH1 or IDH2 gene is mutated in approximately 20% of de novo AML cases, with a higher incidence in CN-AML.1,20,95 Research suggests these are gain-of-function mutations, inhibiting myeloblast maturation downstream.95-97

Due to confounding factors such as co-mutations and varying patient characteristics, researchers are still trying to understand how IDH mutations influence clinical outcomes in AML.38,39

AML, acute myeloid leukemia; CN-AML, cytogenetically normal AML; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2.
It is unclear to what extent RAS mutations affect AML outcomes3,4,41,42

NRAS is one of a family of membrane-associated proteins encoded by RAS oncogenes that are involved in cell proliferation, differentiation, and survival.98,99

Genetic alterations of NRAS occur as activating point mutations, with a reported incidence of approximately 10% to 15%.4,10,20 To date, research has yielded conflicting data about the prognostic impact of RAS mutations in AML.3,4,41,42

AML, acute myeloid leukemia.
TET2 mutations have not been shown to consistently affect clinical outcomes5,6,43

The TET2 enzyme is an epigenetic modifier that may be involved in DNA methylation.100 Genetic alterations in TET2 have been reported in about 8% to 12% of de novo AML cases.6,20 In some studies, TET2 mutations were shown to have a poor prognostic impact; other studies did not demonstrate a prognostic impact.5,6,43

AML, acute myeloid leukemia; TET2, tet methylcytosine dioxygenase 2.
FLT3-TKD mutations have not been definitively linked to poor prognosis1

FLT3 is a ligand-activated receptor tyrosine kinase that is normally expressed by hematopoietic stem/progenitor cells and has important roles in early stages of both myeloid and lymphoid lineage development.16,71,72

Point mutations in the tyrosine kinase domain of FLT3 (FLT3-TKD) occur in approximately 7% of newly diagnosed AML cases, and their impact on prognosis is undetermined.1,45

AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; FLT3-TKD, FLT3 tyrosine kinase domain.
WT1 mutations may have a clinical impact in AML7,46,47

The WT1 gene is believed to regulate transcription of genes involved in cell survival, proliferation, and differentiation.46

Mutations of WT1 have been reported in approximately 6% of de novo AML cases.20,46

While some studies in patients with AML have demonstrated that mutated WT1 has a negative impact on event-free survival and OS, others have not consistently shown it to have a clinical impact.7,46,47

AML, acute myeloid leukemia; OS, overall survival; WT1, Wilms' tumor 1.
EZH2 overexpression has been implicated in disease progression in a variety of cancers101

EZH2 and related EZH1 are epigenetic modifiers that mediate transcriptional silencing and may promote tumorigenesis.102,103 Reports suggest that EZH1 may compensate for EZH2, suggesting that disease progression is dependent on both EZH1 and EZH2.103,104

Mutations of EZH2 are found relatively infrequently in de novo AML, so the prognostic impact of these mutations is not clearly defined.8

AML, acute myeloid leukemia; EZH1, enhancer of zeste 1 polycomb repressive complex 2 subunit; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit.

Listed prevalence estimates are from reports in literature. Exact prevalence has not been clearly established.

ASXL1, additional sex combs–like 1; CEBPA, CCAAT enhancer binding protein alpha; DNMT3A, DNA methyltransferase 3 alpha; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; FLT3-TKD, FMS-like tyrosine kinase 3 tyrosine kinase domain; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; NPM1, nucleophosmin 1; RUNX1, runt related transcription factor 1; TET2, tet methylcytosine dioxygenase 2; TP53, tumor protein p53; WT1, Wilms' tumor 1.

MOLECULAR ANALYSIS
Mutation status should be a key consideration in your treatment strategy; thus, timely molecular testing is crucial at diagnosis and should be considered at relapse1,2,58,105,106

Molecular analysis can identify recurring gene fusions and acquired somatic mutations with prognostic value that may inform treatment pathways.2,105

Due to the potential for clonal evolution of acute myeloid leukemia (AML), the mutations present at relapse may differ from those present at initial diagnosis.58,59,106,107 Thus, it may be important to perform genetic testing multiple times over the course of a disease.

AML, acute myeloid leukemia.

Share your experience
What percentage of your patients with AML receive genetic testing at relapse?
Fewer than 25%
25%-49%
50%-74%
75%-100%

See how others responded:
Reported percentage of patient with AML who have received genetic testing at relapse

UNMET NEEDS
The AML treatment landscape is rapidly evolving

After more than 40 years with limited advances in treatment, recent approvals in acute myeloid leukemia (AML) include a new chemotherapy formulation and targeted therapies.108 However, further treatment options and advances in understanding the biology of AML are still needed.

Examples of the many current challenges and unmet needs in AML include:

Timely molecular analysis

Because genetic testing is no longer purely prognostic, fast processing is important at both diagnosis and relapse to ensure prompt identification of the most appropriate treatment pathway for individual patients.2,105

A standard of care in R/R AML

Therapy for relapsed or refractory (R/R) AML may include intensive or low-intensity chemotherapy with or without stem cell transplant, targeted therapies, enrollment in a clinical trial, or best supportive care, depending on patient- and disease-specific factors.1,2 Patients who may not be able to tolerate intensive salvage chemotherapy do not have many effective treatment options.2

Improved transplant rates

For some patients with intermediate-risk or poor-risk AML, the best hope for long-term survival may be hematopoietic stem cell transplant, which is associated with significant improvement in overall survival and relapse-free survival.109

Tolerable therapies for elderly and/or frail patients

While AML is most frequently diagnosed in people 65 years of age, patients of advanced age and/or those who are deemed unsuitable for intensive chemotherapy may have lower tolerance to cytotoxic agents, limiting treatment options.110,111 These patients may be candidates for therapies that are less intensive, including targeted therapeutic agents, low-intensity chemotherapy, and agents in clinical trials.112

Use of combination therapies

As new therapeutic options become available and treatment strategies develop, future treatment options for some patients with AML may involve using 2 or more therapies with different mechanisms of action. Investigations into the clinical validity of certain combinations are ongoing.113

AML, acute myeloid leukemia; R/R, relapsed or refractory.

Share your experience
What percentage of your patients with AML receive targeted therapy?
Fewer than 25%
25%-49%
50%-74%
75%-100%

See how others responded:
Reported percentage of patient with AML who have received targeted therapy

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