CLASSIFICATION OF AML & - PowerPoint Presentation

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CLASSIFICATION OF AML

&

PROGNOSTIC FACTORS

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Although the first published reports of leukemia occurred in 1845 by Bennett and Virchow, the lack of refined diagnostic methodology limited the distinction between myeloid and lymphoid acute leukemia, With the development of refined staining techniques, followed by microscopy and histochemical staining by the mid-20th century, this distinction was

possible

How Is Acute Myeloid Leukemia Classified?

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Historically, AML was classified by the

morphology

and cytochemical (and later flow cytometric) phenotype of the tumor cells under the French-American-British (FAB) AML classification system.(in 1976 and later revised in 1985)

FAB system divided AML into subtypes,

M0 through M7

, based on the type of cell from which the leukemia develops and how mature the cells are. This was based largely on how the leukemia cells looked under the microscope after routine staining

How Is Acute Myeloid Leukemia Classified?

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The FAB classification system is useful and is still commonly used to group AML into subtypes.

It is very

useful, particularly in its recognition of acute promyelocytic leukemia (AML FAB M3) as a distinct entity.But it doesn’t take into account many of the factors that are now known to affect prognosis .

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The classification of AML has

changed

dramatically over the course of the last several decades, and perhaps more than in any other group of malignancies, the classification of AML is now predicated on identifying the genetic aberrations underlying an individual patient’s diseaseThe purpose of AML classification and genetic testing at diagnosis is largely to risk-stratify patients with AML, and thus help determine appropriate treatment modalities.

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The

World Health Organization (

WHO) has developed a newer system that includes some of these factors to try to better classify AML(1997,2001)WHO classification of AML has since moved toward a system based more on underlying genetics, first incorporating recurrent structural cytogenetic abnormalities, then

specific gene mutations

in the most

recent

2008 edition

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In

2008

, the WHO criteria were revised and included additional entries in the category of AML with recurrent genetic abnormalities. One important revision was to modify "AML with abnormalities of l1q23; MLL" from the previous edition and to change this to t(9;1l)(p22;q23);MLLT3-MLL. This was done to reflect that

all MLL

rearrangements are not identical

. In fact, it is

recommended that variant MLL translocations also be specified in the diagnosis

.

Additional chromosomal rearrangements added

to the most recent

WHO classification include

t( 6;9)

(p23;q34

); DEK-NUP21

,

inv

(3)

(q21q26.2) or

t(3;3)

(q26.2);

RPN1-EVll, and

t(1;22)

(p13;q13);RBM15-MKLl

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AML with recurrent genetic abnormalities

Minor refinements related

to updates in gene names (such as the change from MLL to KMT2A) are included as well as recognition that the inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2) does not represent a fusion gene, but repositions a distal GATA2 enhancer to activate MECOM expression and simultaneously confer GATA2

haploinsufficiency

.

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In order to stress the significance of the

PML-RARA fusion

, which may be cryptic or result from complex cytogenetic rearrangements other than t(15;17)(q24.1; q21.2), acute promyelocytic leukemia (APL) with this fusion is renamed as APLwith PML-RARA. Finally, a new provisional category of

AML with BCR-ABL1

is added to recognize these rare de

novo AML

cases that may benefit from TKI therapy

.

Although

the diagnostic

distinction between de novo AML with BCR-ABL1

and blast

transformation of CML may be difficult without

adequate clinical

information, the significance of detecting this

targetable fusion

is felt

to warrant

a provisional disease category.

Preliminary data suggest

that

deletion of antigen receptor genes (IGH, TCR),

IKZF1 and/or

CDKN2A may support a diagnosis of de novo disease vs BP

of CML.

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The finding

that the

improved prognosis associated with AML with mutated CEBPA is associated with biallelic, but not singleAdditionally, due to the lack of prognostic significance of multilineage dysplasia in patients without MDS-associated cytogenetic findings and with a mutation of NPM1 or biallelic mutation

of

CEBPA, these mutations now supersede

the presence of

multilineage dysplasia in the classification.

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Finally, a provisional category of AML with

mutated

RUNX1 has been added to the classification for cases of de novo AML with this mutation that are not associated with MDS-related cytogenetic abnormalities. This new provisional disease category appears to represent a biologically distinct group with a possibly worse prognosis than other AML types.

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AML with myelodysplasia-related changes

The

presence of multilineage dysplasia alone will not classify a case as AML with myelodysplasia-related changes when amutation of NPM1or biallelic

mutation

of CEBPA

is

present. In cases lacking these

mutations

, the morphologic detection of

multilineage

dysplasia (defined as

the presence

of

50%or more

dysplastic cells in at least 2 cell lines)

remains a

poor prognostic indicator

and is sufficient to make a diagnosis

of AML

with myelodysplasia-related

changes.

A

history of

MDS

remains

as an inclusion criterion for this category as does the

presence of an MDS-related

cytogenetic abnormality

with

1 exception

:

del(9q) has

been removed

as a defining cytogenetic abnormality

forAMLwith

myelodysplasia-related

changes

because of its association with

NPM1 or

biallelic

CEBPA

mutations

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Therapy-related myeloid neoplasms

Therapy-

relatedmyeloid neoplasms (t-MNs) remain as a distinct category in the classification for patients who develop myeloid neoplasms following cytotoxic therapy. The t-MNs may be further subdivided as therapy-related MDS or AML (t-MDS or t-AML), but the associated cytogenetic abnormality, which is important for determining therapy and prognosis, should be identified in the final diagnosis. A number of t-MN cases have been shown to have germ line mutations in cancer susceptibility genes; careful family

histories to

uncover cancer susceptibility are warranted in t-MN patients

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AML, not otherwise specified

Although

the subcategories of AML, not otherwise specified (NOS) lack prognostic significance when cases are classified based on NPM1 mutation and CEBPA biallelic mutation status, the CAC agreed to keep the AML, NOS subcategories with only a single change: The subcategory of acute erythroid leukemia, erythroid/myeloid type(previously defined as a case with >50% BM erythroid precursors and >

20

%

myeloblasts

among nonerythroid cells) has been removed from

the AML category.

In the new classification,

myeloblasts

are always

counted as a percentage of

total marrow

cells and the majority

of such

cases

have

<20

%

total blast cells and are now classified as

MDS (usually

MDS

with excess blasts

).

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Cases

with 50

% or more erythroid cells and >20% total myeloblasts usually meet criteria for AML with myelodysplasia-related changes and should be diagnosed as such; cases with>20% total myeloblasts not meeting criteria for AML with myelodysplasia-related changes or AML with recurrent genetic abnormalities should be categorized as 1 of the other subtypes of AML, NOS. Pure erythroid leukemia

remains

as an AML, NOS subtype and is now the only type

of acute

erythroid leukemia

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Myeloid sarcoma

Myeloid

sarcoma remains in the classification as a unique clinical presentation of any subtype of AML.Myeloid sarcoma may present de novo, may accompany PB and marrow involvement, may present as relapse of AML, or may present as progression of a prior MDS, MPN, or MDS/MPN.Although listed separately in the classification,

cases of

myeloid sarcoma without evidence of marrow disease should

be investigated

comprehensively so that they can be classified into a more specific AML subtype

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Myeloid proliferations of Down syndrome

The

myeloid proliferations of Down syndrome include transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome.Both are usually megakaryoblastic proliferations, with TAM occurring at birth or within days of birth and resolving in 1 to 2 months and myeloid leukemia occurring later, but usually in the first 3 years of life with or without prior TAM and persisting if not treated. The

myeloid neoplasms of Down

syndrome have

a similar behavior that is independent of blast cell count

and these are not subclassified into MDS or AML.

Both

TAM and myeloid leukemia associated with Down syndrome are

characterized by

GATA1 mutations

and mutations of

the

JAK-STAT pathway

, with additional mutations identified in the myeloid

leukemia cases

.

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SINGLE GENE MUTATIONS

Testing

of a number of single genes has been incorporated to further risk-stratify patients, thus providing useful data for therapeutic decisions for the patients with AML with intermediate-risk based on cytogenetics. Testing for these mutations allows reduction of the number of patients in the clinically heterogeneous intermediate-risk subgroup (Figure 2). The currently most important genes to evaluate include the nucleolar protein nucleophosmin

(

NPM1

),

CCAAT/ enhancer-binding protein a (CEBPA), and

fms

-related tyrosine kinase 3 (

FLT3

).

In

addition, mutations of the

vkit

Hardy-Zuckerman

4 feline sarcoma viral

oncogene homolog

(KIT)

modify the prognosis of otherwise

favorable- risk

CBF AML

.

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Mutations in

NPM1

are involved in 25% to 35% of patients with AML and 45% to 64% of patients with AML with normal cytogenetics.The prognostic importance of an NPM1 mutation is dependent upon the mutational status of a second

gene,

FLT3

.

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Internal tandem duplication (

ITD) mutations

of FLT3 are present in approximately 20% of patients with AML, in 28% to 34% of patients with AML with normal cytogenetics, and in 40% of patients with AML with concurrent NPM1 mutation.

The

presence of a

FLT3- ITD

confers an adverse prognosis for those with

intermediate- risk

cytogenetics

and for patients with

NPM1

mutations

,

So testing

of these 2 genes must be

performed together

to provide accurate prognostic information.

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In the

absence of FLT3-ITD mutation

, an NPM1 mutation confers a favorable prognosis for those with normal cytogenetics.Though HSCT is effective in patients with a normal karyotype and NPM1+/FLT3-ITD genotype, retrospective analysis suggests the benefits of HSCT do not outweigh its associated significant morbidity and mortality in this population, while HSCT should be considered

at first remission in other

genotypes.

Recent studies

have suggested that HSCT could still be considered in this population;

however, patients with

NPM1 mutations are often able to have effective salvage

treatment at

relapse, and in general HSCT is initially withheld in

this cohort

.

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Mutations in

CEBPA

are present in 10% to 18% of patients with AML with normal cytogenetics.Whereas a single mutation in CEBPA does not affect prognosis, biallelic mutations confer a favorable prognosis, constitute another provisional WHO AML subtype,and direct consolidative chemotherapy rather than HCST at remission

.

Mutations

in

KIT occur in

20% to 30%

of

CBF AML

cases, which is

typically considered

to be

favorable-risk.

However, the presence

of KIT

mutations confers an

increased

risk of

relapse

Therefore,

CBF AML with KIT mutations

is considered

to be

at

intermediate-risk

in the most recent

National Comprehensive

Cancer Network guidelines.

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Very often, studies exhibit

contradictory results

regarding the prognostic significance of individual genes. The IDH genes and DNMT3A are relevant examples of this phenomenonThe bulk of the current evidence would suggest that IDH1 mutations are associated with a somewhat worse prognosis, while IDH2 mutant effects are codon-dependent

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Another factor that appears to be important in

AML prognostication

is the allele burden of the mutation in question. It is well established that AML specimens contain multiple disease clones at diagnosis, and mutations in signaling genes, such as FLT3 and KIT, are frequently present in only a subset of the malignant blasts at diagnosis.Therefore, it is plausible that a FLT3-ITD mutation present in a small minority of the malignant blasts may not be as prognostically significant as that present in the entirety of the blast

population.

Indeed

, this seems to be the case, as

the adverse

effect of FLT3-ITD mutations

on cytogenetically normal AML appears to

increase with increasing

allele burden

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In some cases of FLT3-ITD–positive AML,

the mutant

allele to wild-type FLT3 ratio is actually greater than 0.5, indicative of loss of heterozygosity at the FLT3 locus, often secondary to duplication of the mutant FLT3 allele. These cases may have a particularly poor prognosis.However, not all studies have confirmed a strong correlation between prognosis and allelic burden, and some recent data suggest that even low-level FLT3-ITD mutant clones at diagnosis may indicate aggressive disease, which would be consistent with the concept that these subclones may be especially chemoresistant

Recently, investigations into the clinical relevance of

WT1

mutations

demonstrated that they were found in 12%

of diagnostic pediatric AML samples.

These mutations were associated with a

normal karyotype (22 %) and FLT3/ITD

, and were found to be an

independent poor prognostic factor

.

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Metaphase

karyotyping is

absolutely necessary, and for those patients with intermediate-risk cytogenetics, molecular assessment of FLT3, NPM1, and CEBPA should be performed. If the patient is found to have CBF AML, KIT should be assessed for mutations

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References

1. Bennett JM,

Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias: French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451–458. 2. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2(7):502–513. 3. Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114(12):2489–2496.4. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354–365.

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5.

Krauth

M-T, Eder C, Alpermann T, et al. High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: frequency and impact on clinical outcome. Leukemia. 2014;28(7):1449–1458. 6. Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100(7):2393–2398. 7. Stein EM, Altman JK, Collins R, et al. AG-221, an oral, selective, first-

inclass

, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2 mutation positive advanced hematologic malignancies. Blood. 2014;124(21):115

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8

.

Linch DC, Hills RK, Burnett AK, Khwaja A, Gale RE. Impact of FLT3ITD mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood. 2014;124(2):273–276. 9. Hirsch P, Labopin M, Marzac C, et al. Impact of FLT3-ITD mutational burden in 469 acute myeloid leukemia (AML) patients. Blood. 2014;124(21): 1033–1033.10. Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in

core-binding

factor

acute myeloid leukemia. Leukemia. 2013;27(9):1891–1901.

11. Sehgal AR, Gimotty PA, Zhao J, et al. DNMT3A mutational status affects the results of dose-escalated induction therapy in acute

myelogenous

leukemia.

Clin

Cancer Res. 2015;21(7):1614–1620.

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12. Gale RE, Green C, Allen C, et al. 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. 2008;111(5):2776–2784.

13. Michael L. Wang, MD, PhD; Nathanael G. Bailey, MD. Acute Myeloid Leukemia

Genetics,Risk Stratification and Implications for Therapy. Arch Pathol Lab Med.2015;139:1215-122314.Daniel A. Arber,1 Attilio Orazi,2 Robert Hasserjian, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. BLOOD,. 2016;127:2391-240515.Hartmut D¨ohner,1 Elihu Estey, et al. David Grimwade,.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. BLOOD, 2017;129;424-447

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