AML is a heterogeneous disease1,2

Dr Pollyea addresses the underlying,
complex genetics of AML

In addition to FLT3 mutations, acute myeloid leukemia (AML) may be characterized by other recurrent cytogenetic and genetic alterations, including1,3-5:

Other mutations
Amplifications
Deletions
Rearrangements
The AML genomes can contain numerous genetic mutations; typically, 1 founder mutation triggers the disease, while other cooperating mutations occur at relapse.6-8
Consider mutational status when2,4,9:
  • Subclassifying AML
  • Predicting prognosis
  • Determining treatment strategies
AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3.

,, AML is genetically heterogeneous, and evidence shows several recurring mutations associated with poor outcomes in patients with newly diagnosed disease and possibly in those with relapsed AML.,,

AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3.

Click on an AML mutation below to learn about its prevalence and prognostic impact.

Tap on an AML mutation below to learn about its prevalence and prognostic impact.


Poor prognosis
FLT3-ITD is one of the worst molecular prognostic factors in AML2,14,15

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.15-17

Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately 25% of newly diagnosed AML cases.2,4,18,19 Compared with FLT3 wild type, FLT3-ITD has been associated with significantly shorter overall survival, remission duration, and disease- or event-free survival.19-24

AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication.
ASXL1 mutations generally carry a poor prognosis26,27

The ASXL1 protein is believed to play a role in epigenetic regulation.28,29 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.25,26,29 These mutations have been associated with unfavorable clinical outcomes, including shortened overall survival, especially in patients with RUNX1 co-mutations.26,27

AML, acute myeloid leukemia; ASXL1, additional sex combs–like 1; RUNX1, runt related transcription factor 1.
Mutated RUNX1 confers a poor prognosis in de novo AML30,31

Transcription factor RUNX1 plays a key role in hematopoietic stem cell emergence and regulation.32-34 It is genetically altered in approximately 10% of de novo AML cases through chromosomal translocations or point mutations.8,30

RUNX1 mutations are associated with fewer responses to induction chemotherapy and shortened overall survival in patients with AML.30,35 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.36

AML, acute myeloid leukemia; RUNX1, runt related transcription factor 1; RUNX1T1, RUNX1 translocation partner 1.
TP53 mutations confer an aggressive disease course and chemotherapy resistance39,40
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 MDM2.41-43 Mutations of TP53 occur in approximately 3% to 8% of AML cases at diagnosis and are commonly associated with complex karyotype AML.8,37,44
AML, acute myeloid leukemia; TP53, tumor protein p53.
KIT mutations may adversely affect clinical outcomes in core binding factor AML (CBF AML)2,46

KIT is a tyrosine kinase receptor believed to be heavily involved in normal hematopoiesis.45 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.8,45

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 overall survival.2,46

AML, acute myeloid leukemia; CBF AML, core binding factor AML.
Generally favorable prognosis
NPM1 mutations are considered driver mutations in AML pathogenesis51

The NPM1 gene has been implicated in ribosome biogenesis and transport, centrosome duplication, and chromatin remodeling, among other cellular events.52-54

Mutations of NPM1 are thought to trigger proliferation and leukemogenesis in myeloid cells; they are present in approximately 28% to 35% of adult AML cases and about 50% of cytogenetically normal AML (CN-AML) cases.2,8,47,55,56

NPM1 mutations are prognostically favorable in the absence of FLT3-ITD mutations48-50

Clinical outcomes for patients with NPM1 mutations are largely dependent on other co-mutations.57 Without concomitant FLT3-ITD mutations, NPM1 mutations are associated with enhanced therapeutic response to induction therapy and, for patients with CN-AML, improved outcomes.48-50

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 AML58,59

CEBPA is a transcription factor thought to be critical to gene expression in hematopoiesis, acting as a differentiation regulator.60 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.8,58 Biallelic mutated CEBPA is considered a favorable prognostic factor.2,9

AML, acute myeloid leukemia; CEBPA, CCAAT enhancer binding protein alpha.
Undetermined prognosis
DNMT3A mutations may be a factor in AML prognosis61-63

The DNMT3A enzyme is an epigenetic modifier and a catalyst for DNA methylation, involved in establishing the patterns of DNA methylation early in embryogenesis.64 Mutations of DNMT3A are considered preleukemic, emerging early on and persisting even during remission.65 They have been reported in about 20% of de novo AML cases, with a higher incidence in cytogenetically normal AML cases.8,66

While some studies demonstrated shorter survival in patients with AML who have mutated DNMT3A, others have not consistently shown it to affect prognosis.61-63,66
AML, acute myeloid leukemia; DNMT3A, DNA methyltransferase 3 alpha.
The prognostic impact of IDH mutations in AML is not well defined68-70

The IDH1 or IDH2 gene is mutated in approximately 20% of de novo AML cases, with a higher incidence in CN-AML.2,8,71 Research suggests these are gain-of-function mutations, inhibiting myeloblast maturation downstream.71-73

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.68,69

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 outcomes74,76-78

NRAS is one of a family of membrane-associated proteins encoded by RAS oncogenes that are involved in cell proliferation, differentiation, and survival.79,80

Genetic alterations of NRAS occur as activating point mutations, with a reported incidence of approximately 10% to 15%.8,74,75 To date, research has yielded conflicting data about the prognostic impact of RAS mutations in AML.74,76-78

AML, acute myeloid leukemia.
TET2 mutations have not been shown to consistently affect clinical outcomes28,81,82
The TET2 enzyme is an epigenetic modifier that may be involved in DNA methylation.84 Genetic alterations in TET2 have been reported in about 8% to 12% of de novo AML cases.8,81 In some studies, TET2 mutations were shown to have a poor prognostic impact; other studies did not demonstrate a prognostic impact.28,81,82
AML, acute myeloid leukemia; TET2, tet methylcytosine dioxygenase 2.
FLT3-TKD mutations have not been definitively linked to poor prognosis2

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.15-17

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.4

AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; FLT3-TKD, FLT3 tyrosine kinase domain.
WT1 mutations may have a clinical impact in AML85-87

The WT1 gene is believed to regulate transcription of genes involved in cell survival, proliferation, and differentiation.85

Mutations of WT1 have been reported in approximately 6% of de novo AML cases.8,85

While some studies in patients with AML have demonstrated that mutated WT1 has a negative impact on event-free survival and overall survival, others have not consistently shown it to have a clinical impact.85-87

AML, acute myeloid leukemia; WT1, Wilms' tumor 1.
EZH2 overexpression has been implicated in disease progression in a variety of cancers89

EZH2 and related EZH1 are epigenetic modifiers that mediate transcriptional silencing and may promote tumorigenesis.90,91 Reports suggest that EZH1 may compensate for EZH2, suggesting that disease progression is dependent on both EZH1 and EZH2.91,92

Mutations of EZH2 are found relatively infrequently in de novo AML, so the prognostic impact of these mutations is not clearly defined.88

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

The genetic landscape of AML is complex. While individual mutations have independent prognostic implications, the presence of co-occurring mutations, or co-mutations, can modulate these implications and may have an impact on optimal patient care. As concurrent mutations build, disease burden increases, which leads to more mutations and treatment resistance.93-95

The content below is supported by reports in literature, but it is not inclusive of all co-mutation combinations possible. While the information is provided to educate, it is not intended to provide any diagnostic or prognostic recommendation; healthcare professionals should use their clinical judgment in the diagnosis and treatment of their patients. The genetic landscape of AML is quickly evolving,94 and as co-mutation patterns are validated in larger prospective clinical trials, Daiichi Sankyo will make every effort to update this information.

FLT3-ITD
DNMT3A
FLT3-ITD and DNMT3A

FLT3 co-mutations hold prognostic significance, and dual mutant FLT3 tends to co-occur most commonly with DNMT3A and NPM1.95

FLT3-ITD and DNMT3A co-mutations occur in 13.3% of patients with cytogenetically normal AML and confer unfavorable outcomes.95

AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication.

FLT3-ITD
NPM1
DNMT3A
FLT3-ITD, NPM1, and DNMT3A

FLT3 co-mutations hold prognostic significance, and dual mutant FLT3 tends to co-occur most commonly with DNMT3A and NPM1.95

FLT3-ITD, NPM1, and DNMT3A co-mutations are associated with poor treatment response and outcomes.95

FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication.

DNMT3A
NPM1
DNMT3A and NPM1

DNMT3A and NPM1 co-mutations are associated with adverse outcomes in patients with cytogenetically normal AML compared with an NPM1 individual mutation.96

AML, acute myeloid leukemia.

FLT3-ITD
NPM1
FLT3-ITD and NPM1

FLT3 co-mutations have prognostic significance. They tend to co-occur most commonly with DNMT3A and NPM1.95

FLT3-ITD and NPM1 co-mutations occur in 40% of patients with cytogenetically normal AML (CN-AML). The presence of an NPM1 mutation is associated with improved prognosis compared with a single FLT3-ITD mutation.95

  • Patients with high FLT3-ITD allelic ratio (>0.5) and mutated NPM1 are classified as intermediate risk9,95

  • Patients with low FLT3-ITD allelic ratio (0.05-0.5) and mutated NPM1 are classified as favorable risk9,95

AML, acute myeloid leukemia; CN-AML, cytogenetically normal AML; DNMT3A, DNA methyltransferase 3 alpha; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication; NPM1, nucleophosmin 1.

ASXL1
RUNX1
ASXL1 and RUNX1

Some studies have shown that ASXL1 and RUNX1 co-mutations confer unfavorable outcomes in patients with AML.26,27

AML, acute myeloid leukemia.

DNMT3A
NPM1
IDH1/IDH2
DNMT3A, NPM1, and IDH1/2

DNMT3A, NPM1, and IDH1/2 co-mutations are associated with inferior overall survival in patients with cytogenetically normal AML (without FLT3-ITD) compared with patients harboring single or double mutations.97

AML, acute myeloid leukemia; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication.

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