Acute myeloid leukemia: Classification

INTRODUCTION — Acute myeloid leukemia (AML) refers to a heterogenous category of clinically aggressive hematologic neoplasms characterized by accumulation of myeloid blasts in bone marrow, blood, and/or other tissues and distinguished by arrested myeloid maturation. In AML, malignant transformation of myeloid-committed progenitor cells impairs maturation of cells that were otherwise destined to give rise to granulocytic, monocytic, erythroid, and/or megakaryocytic elements.

Clinically, AML manifests with symptoms and signs associated with cytopenias (eg, anemia, infections, and/or bleeding or bruising), which may be accompanied by constitutional symptoms, metabolic abnormalities, and various complications. AML has previously been called acute myelogenous leukemia and acute nonlymphocytic leukemia.

Cytogenetic and molecular events associated with AML are key elements in the classification of AML subtypes and have important implications for clinical management.

This topic describes the classification of AML.

Clinical manifestations, diagnosis, pathogenesis, management, and prognosis of AML are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●(See "Acute myeloid leukemia: Pathogenesis".)

●(See "Acute myeloid leukemia: Risk factors and prognosis".)

●(See "Acute myeloid leukemia in adults: Overview".)

CLINICAL PRESENTATION AND DIAGNOSIS — AML typically manifests with symptoms and signs associated with cytopenias, such as anemia, infections, and/or bleeding. These findings may be accompanied by constitutional symptoms, thrombotic or metabolic complications, massive accumulation of blasts in blood (eg, hyperleukocytosis), or other manifestations.

Diagnosis of AML requires evaluation of leukemic blasts from bone marrow, blood, or other disease sites by morphology, immunophenotype, chromosome analysis (karyotype, fluorescence in situ hybridization [FISH]), and molecular testing.

Details of the clinical presentation, initial evaluation, and diagnosis of AML are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

PATHOGENESIS — Development of AML is driven by acquired somatic mutations, along with epigenetic changes in the leukemic cells and alterations in the bone marrow microenvironment. There is increasing recognition of the contributions of inherited (germline) disorders to some cases of AML and related disorders.

AML develops from serial acquisition of mutations in hematopoietic stem and progenitor cells that have the capacity to self-renew and propagate the malignant clone [1,2]. In many cases, clonal hematopoiesis, a common premalignant state that increases in prevalence with age, sets the stage for AML [3]. Mutations in DNMT3A, TET2, and ASXL1 are common in clonal hematopoiesis and appear to be relatively early events in leukemogenesis. Mutations in other genes (eg, FLT3, NRAS, RUNX1) generally arise later.

Somatic mutations in AML are discussed in greater detail separately. (See "Acute myeloid leukemia: Pathogenesis".)

CLASSIFICATION SYSTEMS — Classification schemes for hematologic malignancies continue to evolve with greater insight into pathologic features, pathophysiology, management, and outcomes. Two classification systems for AML were published in 2022 that rely heavily on cytogenetic and molecular features of the leukemic blasts:

●International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemia [4]

●World Health Organization 5th edition (WHO5) myeloid and histiocytic/dendritic neoplasms [5]

Use of either ICC or WHO5 is acceptable. These models supersede earlier systems, including the prior edition of the WHO classification (revised 4th edition; WHO4R) [6].

Both ICC and WHO5 integrate morphology (cytology, histology, tissue architecture), clinical attributes (eg, acute versus chronic, cytopenias/cytoses), lineage (based on immunophenotype), and cytogenetic and molecular features to categorize AML, myelodysplastic syndromes/neoplasms (MDS), and myeloproliferative neoplasms (MPN).

Prior versions of the WHO classification scheme and earlier models (eg, the French-American-British [FAB system] [7], which was prevalent for decades and remains familiar to many clinicians) laid the groundwork for the current models. Earlier systems relied more heavily on clinical features and morphology of leukemic cells, with limited cytogenetic and molecular features.

Further discussion of the ICC and WHO5 classification systems is presented separately. (See "Classification of hematopoietic neoplasms".)

International Consensus Classification — Compared with WHO4R, the ICC moved to a more genetically defined classification system, while retaining many previously defined AML subtypes associated with recurrent/defining genetic abnormalities.

Key features and changes associated with ICC include:

●Blast threshold – Most cases of AML with defining genetic abnormalities can now be diagnosed with ≥10 percent blasts in blood or bone marrow rather than the previous requirement for ≥20 percent blasts. AML with BCR::ABL1 fusion is an exception (ie, requiring ≥20 percent blasts), while AML with mutated TP53, myelodysplasia-related gene mutations, and myelodysplasia-related cytogenetic abnormalities can define subtypes of AML with 10 to 19 percent blasts.

●Myelodysplastic syndromes/neoplasms/AML – This is a new category, in which cases with 10 to 19 percent blasts, but no defining genetic abnormalities, are labeled "MDS/AML." By contrast, WHO5 labels such cases as "MDS with increased blasts-2" (MDS-IB2).

●Diagnostic qualifiers – Prior therapy, antecedent myeloid neoplasms (ie, MDS or MDS/MPN), and predisposing germline genetic disorders are added as descriptive qualifiers to the diagnosis of AML, rather than being designated as unique subtypes.

●TP53 mutations – AML with mutated TP53 is recognized as a distinct entity within a new group of myeloid neoplasms with mutated TP53, which also includes MDS and MDS/AML with mutated TP53. Acute erythroid leukemia (AEL), which nearly always has mutated TP53, was eliminated and subsumed into AML with TP53 mutation. (See 'Mutated TP53' below.)

●CEBPA mutations – AML with in-frame basic leucine zipper (bZIP) mutations of CEBPA no longer requires biallelic mutations. (See 'Mutated CEBPA' below.)

●Subtypes redefined – AML with somatic RUNX1 mutation was included in the broad category of AML with myelodysplasia-related gene mutations. Both ICC and WHO5 recognize that morphologic dysplasia alone is no longer sufficient for a diagnosis of AML with myelodysplasia-related changes.

●Special categories – Presence of an extramedullary mass of myeloid blasts (myeloid sarcoma) is sufficient to diagnose AML. (See 'Myeloid sarcoma' below.)

Myeloid neoplasms associated with Down syndrome and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are considered distinct diagnoses. (See 'Myeloid proliferations related to Down syndrome' below and 'Other AML subtypes in International Consensus Classification' below.)

World Health Organization 5th edition — WHO5 emphasizes genetically defined criteria for classification of AML, while cases without such features are classified according to the differentiation of the leukemic blasts. AML is organized according to the following major groups by WHO5:

●AML with defining genetic abnormalities – WHO5 eliminated the 20 percent blast threshold for the diagnosis of AML with defining genetic abnormalities.

However, the 20 percent blast threshold was retained for AML with CEBPA mutations (to distinguish this from MDS with mutated CEBPA) and for AML with BCR::ABL1 (to avoid overlap with chronic myeloid leukemia [CML] presenting in advanced phase of disease).

WHO5 also created a new subtype, called AML with other defined genetic alterations, which serves as a landing spot for new and/or uncommon AML subtypes, which require further confirmation in future studies.

●AML defined by differentiation – For AML that lacks a defining genetic abnormality, AML subtypes are labeled according to the state of differentiation. All such cases require ≥20 percent blasts, except for AEL. (See 'Other AML subtypes in World Health Organization 5th edition' below.)

WHO5 labels cases with no defining genetic abnormality but with 10 to 19 percent blasts as MDS-IB2; this differs from ICC, which labels such cases as MDS/AML.

●Subtypes eliminated – WHO5 eliminated AML, not otherwise specified (AML, NOS), which was replaced by subtypes according to the stage of differentiation. (See 'Other AML subtypes in World Health Organization 5th edition' below.)

Comparison of International Consensus Classification and World Health Organization 5th edition — ICC and WHO5 have similar, but distinct, systems for organizing categories of AML, and they differ regarding certain diagnostic criteria and labels for subtypes.

Neither system requires ≥20 percent blasts for many AML with defining genetic abnormalities, and both eliminated AML with myelodysplasia-related changes and AML with somatic RUNX1 mutation.

Key differences between ICC and WHO5 include:

●AML with defining genetic characteristics – Both systems classify most cases of AML according to a defining genetic abnormality. (See 'AML with defining genetic abnormalities' below.)

•International Consensus classification – More specific labels are used for certain subtypes with defining genetic abnormalities. As an example, acute promyelocytic leukemia (APL) with t(15;17)/PML::RARA is distinct from APL with other RARA rearrangements; by contrast, all cases of APL are grouped as a single subtype by WHO5.

•World Health Organization 5th edition – A new category, AML with other defined genetic abnormalities, serves as a placeholder for AML with uncommon genetic findings that require further characterization and confirmation.

●AML without defining genetic abnormalities – With more subtypes based on distinctive genetic characteristics, the fraction of cases without a defining genetic abnormality decreased substantially in both systems.

•International Consensus Classification – AML, NOS was retained as a subtype for cases with ≥20 percent blasts but no defining genetic abnormality. Cases with 10 to 19 percent blasts are now described as MDS/AML.

•World Health Organization 5th edition – AML, NOS was eliminated as a category and replaced with eight subtypes that are defined by the state of differentiation. (See 'Other AML subtypes in World Health Organization 5th edition' below.)

Pure erythroid leukemia, which almost always has mutated TP53, was eliminated in ICC and is, instead, subsumed into AML with TP53 mutation. WHO5 retained this as a differentiation-based category, now labeled AEL.

●Therapy-related AML – AML that arises after cytotoxic treatment generally carries an adverse prognosis. (See 'Therapy-related AML' below.)

For such cases:

•International Consensus Classification – "Therapy-related" is added as a qualifier after a diagnosis of AML, MDS, or MDS/AML.

•World Health Organization 5th edition – Treatment-related myeloid neoplasms constitute a new subtype, "myeloid neoplasms postcytotoxic therapy" that is included among "secondary myeloid neoplasms." Assignment to subtypes in this category is based on medical history rather than morphologic and/or genetic features.

●Myeloid neoplasms with mutated TP53 – Mutations of TP53 carry an adverse prognosis. (See 'Mutated TP53' below.)

For such cases:

•International Consensus Classification – A new category, "myeloid neoplasms with TP53 abnormalities" includes subtypes that are classified according to the percentage of blasts (ie, <10 percent [MDS], 10 to 19 percent [MDS/AML], ≥20 percent [AML]).

•World Health Organization 5th edition – Myeloid neoplasms with TP53 abnormalities are labeled as AML or MDS according to the percentage of blasts. AML with TP53 mutations is described in multiple categories, including AEL and secondary myeloid neoplasms.

●Disorders associated with germline pathogenic gene variants. (See 'Predisposing genetic conditions' below.)

•International Consensus Classification – A new category, "pediatric and/or germline mutation-associated disorders," includes disorders such as juvenile myelomonocytic leukemia.

•World Health Organization 5th edition – "Associated with germline (gene) variant" is added as a modifier to the category label (eg, AML, MPN, MDS).

●Myeloid proliferations related to Down syndrome. (See 'Myeloid proliferations related to Down syndrome' below.)

•International Consensus Classification – Myeloid proliferations associated with Down syndrome comprise a new category in ICC that includes transient abnormal myelopoiesis (TAM) associated with Down syndrome and myeloid leukemia associated with Down syndrome.

•World Health Organization 5th edition – These disorders are included in "myeloid neoplasms associated with germline predisposition."

Implications for clinicians — In general, differences between the ICC and WHO5 classification systems are modest, but they have implications for clinicians. Importantly, both systems recognize the biologic and clinical overlap between advanced stages of MDS and AML with lower blast counts and certain genetic findings (eg, mutated TP53) that confer a poor prognosis.

However, the following distinctions between ICC and WHO5 should be kept in mind:

●Clinical trials – The different defining blast thresholds that distinguish MDS from AML may affect eligibility criteria in future clinical trials.

Nevertheless, contemporary trials increasingly permit enrollment of patients with advanced MDS in AML trials. The implications of different diagnostic thresholds between ICC and WHO5 were acknowledged in WHO5, which stated, "there was broad agreement that MDS-IB2 may be regarded as AML-equivalent for therapeutic considerations and from a clinical trial design perspective when appropriate" [5].

●Clinical care – For nonprotocol-directed clinical care, treatment decisions should continue to be guided by medical comorbidities, age, and cytogenetic and molecular prognostic factors rather than the labels MDS or AML, per se. These treatment decisions are often difficult, but the distinction between >10 percent blasts and >20 percent blasts should only infrequently be the deciding factor in guiding management of such patients.

This importance of age, fitness, and genetic features for guiding treatment decisions is especially important for less-fit individuals, as discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults".)

AML WITH DEFINING GENETIC ABNORMALITIES — The large category of AML with defining genetic abnormalities accounts for most cases of AML in both the International Consensus Classification (ICC) and World Health Organization 5th edition (WHO5) systems.

Most cases of AML with defining genetic abnormalities can be diagnosed with ≥10 percent blasts in marrow or blood. Notable exceptions are AML with:

●BCR::ABL1 fusion (in both ICC and WHO5).

●Mutated TP53 (in ICC; labeled AML with ≥20 percent blasts versus MDS/AML for cases with 10 to 19 percent blasts).

●Myelodysplasia-related gene mutations (in ICC; ie, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2, which are distinguished from MDS/AML with 10 to 19 percent blasts).

●Myelodysplasia-related cytogenetic abnormalities (in ICC; defined by a complex karyotype [≥3 unrelated clonal chromosomal abnormalities in the absence of other class-defining recurring genetic abnormalities], del[5q]/t[5q]/add[5q], -7/del[7q], +8, del[12p]/t[12p]/add[12p], i[17q], -17/add[17p] or del[17p], del[20q], and/or idic[X][q13] clonal abnormalities), which are distinguished from cases of MDS/AML with myelodysplasia-related cytogenetic abnormalities (10 to 19 percent blasts).

●AML, not otherwise specified (AML, NOS; in ICC, which are distinguished from MDS/AML with 10 to 19 percent blasts).

●AML with CEBPA mutation (in WHO5).

There are also differences in the naming of these subtypes (eg, ICC includes the characteristic chromosomal and molecular rearrangement for many subtypes, whereas WHO5 labels include only the molecular rearrangements).

The following are categories of AML with defining genetic abnormalities, noting significant differences between the systems.

Acute promyelocytic leukemia with PML::RARA — Acute promyelocytic leukemia (APL) with PML::RARA is a unique clinicopathologic entity that often presents with a coagulopathy and is characterized by the infiltration of the bone marrow by promyelocytes with the PML::RARA fusion gene [6]. The rearrangement links the retinoic acid receptor alpha (RARA) gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15, and it is uniquely responsive to treatment with all-trans retinoic acid.

●Differences between International Consensus Classification and World Health Organization 5th edition

•International Consensus Classification – Distinguishes APL with t(15;17)(q24.1;q21.2)/PML::RARA versus cases of APL with other RARA rearrangements.

•World Health Organization 5th edition – Describes only one subtype (ie, APL with PML::RARA fusion).

●Clinical – Cases are frequently associated with disseminated intravascular coagulation (DIC) and fibrinolysis. APL with PML::RARA accounts for up to 13 percent of newly diagnosed AML [8]. Clinical manifestations of APL are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Clinical features'.)

●Bone marrow appearance – Abnormal promyelocytes predominate in the marrow. There are hypergranular or microgranular variants of APL.

●Myeloblasts – A characteristic folded, reniform (kidney-shaped), or bilobed nucleus may be found in promyelocytes; coarse azurophilic granules and multiple Auer rods are also common (picture 1). Cytoplasmic granules in promyelocytes may be so prominent that they obscure the nuclear-cytoplasmic border. The less-common microgranular variant of APL contains smaller, less-apparent cytoplasmic granules and bilobed nuclei (picture 2), which can occasionally be confused with monocytic morphology.

●Immunophenotype – Hypergranular variants are CD33 positive, CD64 positive; have variable levels of CD13 expression; low expression of HLA (human leukocyte antigen)-DR, CD34, and leukocyte integrins (CD11a, CD11b, CD18); and usually present with low white blood cell (WBC) counts. Microgranular variants can have CD34 or CD2 expression on some cells and often present with high WBC counts.

●Cytogenetics – Nearly all cases are associated with t(15;17)(q24.1;q21.2), but the WHO5 nomenclature recognizes that PML::RARA may also result from complex cytogenetic rearrangements. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 't(15;17); PML::RARA'.)

Cases with morphology resembling APL, but with variant translocations that are not uniformly responsive to retinoic acid [9], are labeled APL with other RARA rearrangements in ICC but are classified as APL in WHO5.

●Prognosis – There is risk of early death from DIC, but treatment using all-trans retinoic acid, with or without arsenic trioxide, is usually associated with favorable outcomes. APL represents a medical emergency, but if managed appropriately, it has a favorable prognosis.

Management of APL is presented separately. (See "Initial treatment of acute promyelocytic leukemia in adults".)

t(8;21)/RUNX1::RUNX1T1 — The finding of t(8;21)(q22;q22), RUNX1::RUNX1T1 is diagnostic for AML, in the presence of ≥10 percent blasts.

AML with t(8;21) identifies a morphologically and clinically distinct subset of AML with the following features [6,10]:

●Clinical – The balanced translocation t(8;21)(q22;q22), RUNX1::RUNX1T1 (previously AML1::ETO), accounts for 7 percent of adults with newly diagnosed AML (figure 1) [8]. t(8;21) is the most frequent cytogenetic abnormality in children with AML (12 to 15 percent) [11,12]. Myeloid sarcoma can be present at diagnosis. Compared with other subtypes, patients with AML with RUNX1::RUNX1T1 may have lower leukocyte counts, hemoglobin, and blast counts [13,14].

●Bone marrow appearance – This subtype has no diagnostic morphologic features, but promyelocytes, myelocytes, and metamyelocytes are present and may sometimes include fine Auer rods. Eosinophils may be increased but show no morphologic abnormalities.

●Myeloblasts – The large myeloblasts tend to have indented nuclei, abundant basophilic cytoplasm with numerous azurophilic granules, and a prominent paranuclear clear zone. Auer rods, which appear as single long rods with tapered ends, are common and may be found in blasts and maturing neutrophils. Abnormal nuclear segmentation (pseudo-Pelger-Huët nuclei), very large cytoplasmic granules (pseudo-Chediak-Higashi granules), and/or abnormal cytoplasmic staining (eg, homogeneous, salmon-colored cytoplasm with blue rims in maturing neutrophils) may be seen, but dysplasia in other lineages is uncommon.

●Immunophenotype – Most cases have a subpopulation of blasts that express abundant CD34, HLA-DR, myeloperoxidase (MPO), and CD13 but weak expression of CD33 [15]. This leukemia can coexpress lymphoid markers (eg, CD19, PAX5, cytoplasmic CD79) [16-18], but this should not be construed as evidence for a mixed phenotype. CD56 is expressed in a fraction of cases.

●Cytogenetics – Even if t(8;21) is not observed by karyotypic analysis, fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) demonstrate the cryptic RUNX1::RUNX1T1 rearrangement. More than two-thirds of cases show additional cytogenetic abnormalities, including loss of a sex chromosome or del(9q) [19]. Further description of this translocation is presented separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 't(8;21); RUNX1::RUNX1T1'.)

●Prognosis – This leukemia is associated with a favorable prognosis [20]. The presence of KIT mutations is an adverse prognostic feature in patients with t(8;21). Patients can have RUNX1-RUNX1T1 transcripts detected by RT-PCR, even when they have been in remission for many years; this finding does not always predict relapse [21].

Familial platelet disorder with propensity to myeloid malignancies is an autosomal dominant syndrome caused by germline monoallelic mutations in RUNX1 that typically presents with longstanding mild to moderate thrombocytopenia, a mild bleeding propensity (due to an aspirin-like functional platelet defect), and increased risk of developing MDS, AML, and T cell acute lymphoblastic leukemia (ALL). This familial disorder is discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial platelet disorder with propensity to myeloid malignancies (FPD)'.)

inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::B-MYH11 — AML with these chromosome 16 abnormalities usually exhibit monocytic and granulocytic differentiation with morphologically abnormal eosinophils. These leukemias were previously classified as acute myelomonocytic leukemia with abnormal eosinophils (AMML; FAB M4Eo).

●Clinical – Abnormalities of chromosome 16 are seen in approximately 5 percent of adults with newly diagnosed AML (figure 1) [8]. It is more common in younger patients and can present as an extramedullary myeloid sarcoma; some studies have reported an increased incidence of central nervous system involvement [22,23].

●Bone marrow appearance – In addition to the typical morphologic features of AML, bone marrow demonstrates abnormal eosinophils, including all stages of eosinophilic maturation (ie, there is generally no maturation arrest) and immature eosinophilic granules seen in the promyelocyte and myelocyte stages of development [24].

●Myeloblasts – Myeloblasts have a significant monocytic component (which may be nonspecific esterase [NSE] reaction negative). There are variable numbers of abnormal immature eosinophils with large, atypical, purple-violet cytoplasmic granules (picture 3).

●Immunophenotype – The immunophenotype is often complex with multiple blast populations: immature blasts (CD34 positive, CD117 positive) and populations that are more granulocytic (expression of CD13, CD33, CD15, CD65, and/or MPO) or monocytic (expression of CD14, CD4, CD11b, CD11c, CD64, CD36, and/or lysozyme).

●Cytogenetics – AML with inv(16)(p13.1q22) accounts for the majority of this AML subtype; t(16;16)(p13.1;q22); CBFB::MYH11 is much less common. Further details regarding these translocations are presented separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 'inv(16) or t(16;16); CBFB::MYH11'.)

●Prognosis – This leukemia is associated with more favorable outcomes, but cases with a KIT mutation may do more poorly [25].

t(9;11)(p21.3;q23.3); MLLT3::KMT2A — This subtype is associated with KMT2A::MLLT3 fusion and generally has monocytic features.

●Differences between International Consensus Classification and World Health Organization 5th edition

•International Consensus Classification – Distinguishes between cases with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A versus other KMT2A rearrangements.

•World Health Organization 5th edition – Labeled AML with KMT2A rearrangement.

●Clinical – t(9;11) is more common in children (9 to 12 percent) than in adults (2 percent) [8,24]. Patients may present with DIC, infiltration of gingiva or skin with leukemic cells, or myeloid sarcoma.

●Bone marrow appearance – Monoblasts and promonocytes usually predominate in the marrow; promonocytes are considered blast equivalents. Monoblasts and promonocytes stain with NSE.

●Immunophenotype – Most pediatric cases express HLA-DR, CD33, CD65, and CD4, with low level expression of myeloid markers (eg, CD13, CD14) [26]. Adult cases express more markers of monocytic differentiation, with variable expression of CD34 and CD117 [27].

●Cytogenetics – t(9;11)(p21.3;q23.3) may be accompanied by secondary cytogenetic abnormalities, such as gain of chromosome 8 [28,29].

KMT2A (previously known as ALL-1 or MLL-1) has been involved in >80 different translocations [30]. Further details regarding translocations involving KMT2A are presented separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 't(9;11); KMT2A::MLLT3'.)

●Prognosis – t(9;11)(p21.3;q23.3) is associated with an intermediate survival.

AML with t(6;9)(p22.3;q34.1)/DEK::NUP214 — This subtype is associated with the DEK::NUP214 rearrangement and can exhibit monocytic features, basophilia, or multilineage dysplasia.

●Clinical – This subtype is seen in 1 percent of adults and 10 percent of children with newly diagnosed AML [8,31]. Patients may present with pancytopenia and lower leukocyte counts than other AML subtypes [32].

●Bone marrow appearance – Bone marrow presents with variable morphology, basophilia, and single or multilineage dysplasia [33,34].

●Myeloblasts – Myeloblasts are positive for MPO.

●Immunophenotype – The tumor cells typically express CD13, CD33, CD38, CD45, and HLA-DR.

●Cytogenetics – There is a high incidence of FLT3 internal tandem duplications (ITD) [33]. Details of this translocation are presented separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 't(6;9); DEK::NUP214'.)

●Prognosis – AML with t(6;9)(p23;q34); DEK-NUP214 has a poor prognosis [8,31,34].

inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM — These karyotypic findings are associated with deregulated expression of MECOM (also called EVI1); patients may present with normal or elevated platelet counts.

●Differences between International Consensus Classification and World Health Organization 5th edition

•International Consensus Classification – Distinguishes between AML with inv(3)(q21.3q26.2) or AML with t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1) versus AML with other MECOM rearrangements.

•World Health Organization 5th edition – This is a single subtype in WHO5.

●Clinical – This subset accounts for 1 to 2 percent of AML [28,35]. Giant, hypogranular platelets are common, and megakaryocytic nuclei and hypogranular neutrophils with pseudo-Pelger-Huët anomaly may be seen in blood.

●Bone marrow appearance – Megakaryocytes may be dysplastic and increased in number, with nonlobated or bilobed nuclei [36-38]. There may be multilineage dysplasia in nonblast cells. Cellularity and fibrosis are variable, and eosinophils, basophils, or mast cells may be increased in the marrow.

This abnormality may be seen in de novo AML and in therapy-related MDS/AML. (See 'Therapy-related AML' below.)

●Myeloblasts – Blasts may be variable in appearance, with minimal differentiation and myelomonocytic or megakaryoblastic features.

●Immunophenotype – Blasts are positive for CD34, CD33, CD13, CD117, and HLA-DR; most express CD38. A subset of cases expresses megakaryocytic markers (eg, CD41, CD61).

●Cytogenetics – A variety of abnormalities of the long arm of chromosome 3 may be found (figure 1). The abnormalities reposition an enhancer of GATA2 to activate MECOM expression and result in functional haploinsufficiency of GATA2 [39,40].

A familial form of AML caused by monoallelic mutations in GATA2 is discussed in more detail separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial MDS/AML with mutated GATA2'.)

●Prognosis – This is an aggressive subset of AML with generally poor prognosis [41-44].

BCR::ABL1 — This category requires ≥20 percent blasts in both ICC and WHO5.

The Philadelphia chromosome, t(9;22)(q34;q11.2), or BCR::ABL1 gene rearrangement is found in a small percentage of patients with apparently de novo AML (2 percent), a higher percentage of patients with mixed-phenotype acute leukemia (38 percent), and is associated with adverse outcomes [45,46]. On genomic analysis, these cases display some abnormalities also seen in ALL, including deletions in IKZF1 and CDNK1A/B [47]. Unlike chronic myeloid leukemia (CML; at any phase), cases of AML and ALL with BCR::ABL1 display concomitant loss of IGH/VDJ and TARP regions; these findings support the identification of AML with BCR::ABL1 as an entity that is distinct from CML myeloid blast crisis.

CML blast crisis is discussed separately. (See "Treatment of chronic myeloid leukemia in blast crisis".)

Mutated NPM1 — Nucleophosmin gene (NPM1) abnormalities define a subtype of AML but may also be seen in cases of MDS or chronic myelomonocytic leukemia.

●Clinical – NPM1 mutation is found in 2 to 8 percent of childhood AML and 27 to 35 percent of adult AML [48]. Patients often have higher WBC counts than other subtypes of AML [49]. There may be extramedullary involvement (eg, gingiva, skin, lymph nodes).

●Bone marrow – The bone marrow is hypercellular, and blasts frequently exhibit myelomonocytic or monocytic features. Multilineage dysplasia is present in one-quarter of cases.

●Immunophenotype – Immunostaining with anti-NPM1 antibodies reveals involvement of ≥2 lineages in most cases [50]. Blasts express CD33 and may express CD117, CD123, and CD110 [51].

●Prognosis – The presence of the NPM1 mutation generally confers a favorable prognosis; however, when mutated NPM1 occurs in conjunction with mutations in FLT3, the prognosis is worse than in patients who only have the NPM1 mutation [6,10,48]. The prognostic impact of NPM1 mutations is discussed in more detail separately. (See "Acute myeloid leukemia: Risk factors and prognosis", section on 'NPM1'.)

Mutated CEBPA — This subtype is defined by a basic leucine zipper (bZip) mutation of CEBPA. Most cases of AML with mutated CEBPA exhibit little maturation, but some manifest myelomonocytic or monoblastic features.

●Differences between International Consensus Classification and World Health Organization 5th edition – Biallelic bZip CEBPA mutations are no longer required in either ICC or WHO5 (ie, a single mutation in the bZip region is sufficient for diagnosis).

•International Consensus Classification – Diagnosis requires ≥10 percent blasts.

•World Health Organization 5th edition – AML with CEBPA mutation can be diagnosed irrespective of the blast count, with appropriate clinicopathologic correlation.

●Clinical – Biallelic mutations of CEBPA are present in 4 to 9 percent of children and young adults [52,53]; it is less common in older patients. Patients may present with a higher level of hemoglobin and lower platelet counts than other AML.

●Bone marrow – There are no distinctive morphologic features. Most cases exhibit little or no maturation, and multilineage dysplasia is present in one-quarter of cases [52,53].

●Immunophenotype – Cases with biallelic CEBPA mutation have little or no expression of some monocytic markers, such as CD14. There may be significant expression of CD7, CD15, CD64, and HLA-DR [52,53].

●Prognosis – This subtype of AML is associated with a favorable prognosis. The prognostic impact of CEBPA mutations is discussed in more detail separately. (See "Acute myeloid leukemia: Risk factors and prognosis", section on 'CEBPA'.)

Familial AML with mutated CEBPA is discussed in more detail separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial AML with mutated CEBPA'.)

Mutated TP53 — ICC and WHO5 differ in how they label AML with TP53 mutations. TP53 mutations negatively influence prognosis of myeloid neoplasms independent of the blast count, and they may arise in the setting of previous cytotoxic treatments, germline disorders, MDS, or without any predisposing condition.

●Differences between International Consensus Classification and World Health Organization 5th edition – ICC and WHO5 differ in how they classify AML with mutated TP53. ICC created a new category, "myeloid malignancies with TP53 abnormalities." By contrast, WHO5 does not have a specific category for cases with mutated TP53 but acknowledges that many patients are included among those with 17p abnormalities or therapy-related secondary AML.

•International Consensus Classification – ICC created a new category, "myeloid malignancies with TP53 mutations," in recognition of the shared biology and treatment responses of these conditions. It further subclassifies them according to the percentage of blasts, as follows:

-MDS with mutated TP53 – <10 percent blasts with multihit TP53 mutation (ie, two distinct TP53 mutations, each with variant allele fraction [VAF] >10 percent or a single TP53 mutation with either 17p deletion, VAF >50 percent, or copy-neutral loss of heterozygosity at the 17p TP53 locus)

-MDS/AML with mutated TP53 – 10 to 19 percent blasts

-AML with mutated TP53 – >20 percent blasts

While mutations of both TP53 alleles are required to diagnose MDS with mutated TP53, any pathogenic TP53 mutation with VAF >10 percent is sufficient to diagnose AML and MDS/AML with mutated TP53.

•World Health Organization 5th edition – Myeloid disorders with TP53 mutations are included in various categories of AML or MDS. There is no specific subtype of AML with mutated TP53 in WHO5, but the monograph acknowledges that MDS with multiple TP53 abnormalities may be regarded as being equivalent to AML for treatment purposes.

Myelodysplasia-related gene mutations — The following mutations are considered myelodysplasia-related in both ICC and WHO5: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2.

●Differences

•International Consensus Classification – In addition to those listed above, RUNX1 mutations are considered myelodysplasia related. ICC distinguishes cases according to the percentage of blasts:

-AML with myelodysplasia-related mutations – ≥20 percent blasts

-MDS/AML with myelodysplasia-related mutations – 10 to 19 percent blasts

•World Health Organization – In the presence of ≥20 percent blasts, the mutations listed above are sufficient to diagnose AML with myelodysplasia-related gene mutation.

In WHO, morphology alone is no longer sufficient to diagnose myelodysplasia-related AML; this subtype and AML with myelodysplasia-related cytogenetic abnormalities replaced the former category, "AML, myelodysplasia-related." (See 'Myelodysplasia-related cytogenetic abnormalities' below.)

Myelodysplasia-related cytogenetic abnormalities — The following karyotypic abnormalities are considered myelodysplasia-related in both ICC and WHO5: complex karyotype (≥3 unrelated clonal chromosomal abnormalities), del(5q)/t(5q)/add(5q), -7/del(7q), +8, del(12p)/t(12p)/add(12p), i(17q), -17/add(17p) or del(17p), del(20q), and/or idic(X)(q13) clonal abnormalities.

●Differences

•International Consensus classification – ICC distinguishes such cases according to the percentage of blasts:

-AML with myelodysplasia-related cytogenetic abnormalities – ≥20 percent blasts

-MDS/AML with myelodysplasia-related cytogenetic abnormalities – 10 to 19 percent blasts

•World Health Organization – This subtype is defined as a malignancy with ≥20 percent blasts expressing a myeloid immunophenotype and harboring the designated cytogenetic abnormalities associated with MDS, which arise de novo or following a known history of MDS or MDS/myeloproliferative neoplasms (MPN).

Other genetic abnormalities — Less common mutations are categorized differently by ICC and WHO5.

●International Consensus Classification – AML with other rare recurring translocations require ≥10 percent blasts and are classified as "AML with other rare recurring translocations."

●World Health Organization 5th edition – The following are considered separate subtypes in WHO5:

•AML with RBM15::MRTFA fusion

•AML with NUP98 rearrangement

•AML with other defined genetic alterations

OTHER SUBTYPES — Cases of AML that do not meet the criteria for defining genetic abnormalities are classified differently by the International Consensus Classification (ICC) and World Health Organization 5th edition (WHO5).

AML with defining genetic abnormalities is described above. (See 'AML with defining genetic abnormalities' above.)

Other AML subtypes in International Consensus Classification — Classification of cases of AML that do not have defining genetic abnormalities and certain other categories of myeloid malignancies are described as follows:

●AML, not otherwise specified – ICC retained the category AML, not otherwise specified (AML, NOS) to accommodate cases that do not meet the criteria for defining genetic abnormalities. Such cases are stratified according to the percentage of blasts:

•AML, not otherwise specified – ≥20 percent blasts

•Myelodysplastic syndromes/neoplasms/AML, not otherwise specified – 10 to 19 percent blasts

AML in patients with a history of prior cytotoxic therapy, antecedent myeloid neoplasms (ie, myelodysplastic syndromes/neoplasms [MDS] or MDS/myeloproliferative neoplasms [MPN]), or an underlying predisposing germline genetic disorder is identified with diagnostic qualifiers, rather than as specific disease categories. As a result, therapy-related myeloid neoplasms and AML with myelodysplasia-related changes were eliminated as designated subtypes. Such cases are described below. (See 'Therapy-related AML' below.)

AML with mutated TP53 is a separate entity within the group of myeloid neoplasms with mutated TP53, which also includes MDS and MDS/AML with mutated TP53. (See 'Mutated TP53' above.)

●Myeloid Sarcoma – An extramedullary mass of myeloid blasts that effaces the normal tissue architecture, as described below. (See 'Myeloid sarcoma' below.)

●Down syndrome-related myeloid neoplasms – Myeloid proliferations related to Down syndrome, including AML, constitute a distinct category in ICC. (See 'Myeloid proliferations related to Down syndrome' below.)

●Blastic plasmacytoid dendritic cell neoplasm – Blastic plasmacytoid dendritic cell neoplasm (BPDCN) can present with circulating malignant cells but is distinct from AML, as discussed separately. (See "Blastic plasmacytoid dendritic cell neoplasm".)

Other AML subtypes in World Health Organization 5th edition — In WHO5, cases that do not have a defining genetic abnormality are categorized according to the level of differentiation of the leukemic cells. The 20 percent threshold to distinguish MDS from AML remains for cases that do not have defining genetic abnormalities; this contrasts with ICC, in which cases with 10 to 20 percent blasts are labeled MDS/AML. (See 'Other AML subtypes in International Consensus Classification' above.)

AML with minimal differentiation — This category corresponds to 6 percent of cases of what was previously labeled AML, NOS [54].

The leukemic blasts are minimally differentiated, with no cytoplasmic granules or Auer rods, and they cannot be distinguished microscopically from lymphoblasts (picture 4) [55-57].

Diagnostic criteria include [5]:

●Blasts are negative (<3 percent) for myeloperoxidase (MPO) by cytochemistry

●Expression of ≥2 myeloid-associated antigens, such as CD13, CD33, and CD117

Blasts generally express antigens of early hematopoiesis (eg, CD34, CD117, and CD33) but lack antigens of more mature myeloid cells (eg, CD14, CD15, CD11b, CD64). Expression of terminal deoxynucleotidyl transferase (TdT) and the T cell antigen CD7 may be present.

AML without maturation — This category corresponds to 25 percent of what was previously labeled AML, NOS and 5 to 10 percent of cases of AML [54].

Blasts account for >90 percent of total cells. The blasts are large with grayish-blue cytoplasm and large nuclei with prominent nucleoli (picture 5). Some cases contain azurophilic granules and/or Auer rods.

Diagnostic criteria for AML without maturation are [5]:

●≥3 percent blasts positive for MPO (by immunophenotyping or cytochemistry) and negative for nonspecific esterase (NSE) by cytochemistry

●Maturing cells of the granulocytic lineage constitute <10 percent of nucleated bone marrow cells

Many cases express antigens of early hematopoiesis (eg, CD34, CD38, human leukocyte antigen [HLA]-DR) and one or more myeloid-associated antigens (eg, CD13, CD33, CD117), but markers of granulocytic maturation (eg, CD15, CD65) are not expressed in most cases.

AML with maturation — This category accounts for 10 percent of cases of AML.

Blasts account for <90 percent of the marrow cellularity, and maturation is defined by presence of ≥10 percent of bone marrow cells that exhibit differentiation to promyelocytes, myelocytes, and/or mature neutrophils. Blasts may or may not have azurophilic granules and/or Auer rods (picture 6) [58].

Diagnostic criteria for AML with maturation are [5]:

●≥3 percent blasts positive for MPO (by immunophenotyping or cytochemistry) or SBB by cytochemistry.

●Maturing cells of the granulocytic lineage constitute ≥10 percent of nucleated bone marrow cells.

●Cells of monocyte lineage constitute <20 percent of bone marrow cells.

●Expression of ≥2 myeloid-associated antigens, such as MPO, CD13, CD33, and CD117.

Blasts may also express antigens of early hematopoiesis (eg, CD34, CD38, HLA-DR) and those associated with granulocytic maturation (CD65, CD11b, and CD15), but monocytic markers (eg, CD14, CD64) are usually negative.

Acute basophilic leukemia — This is a very rare category of AML in which differentiation is primarily toward basophils. Circulating blasts contain moderately basophilic cytoplasm with variable numbers of coarse basophilic granules that are positive for metachromatic staining with toluidine blue [6]. Clinically, there may be cutaneous involvement, organomegaly, lytic bone lesions, and/or symptoms related to hyperhistaminemia.

Diagnostic criteria for acute basophilic leukemia are [5]:

●Blasts and immature/mature basophils exhibit metachromasia with toluidine blue staining.

●Blasts are negative for cytochemical MPO and NSE.

●No expression of strong CD117 equivalent (to exclude mast cell leukemia).

Acute myelomonocytic leukemia — This category accounts for 21 percent of AML, NOS [54] and 5 to 10 percent of all AML.

The monocytes can be recognized morphologically (picture 7) by staining with NSE or by immunophenotype (eg, expression of CD14, CD11c, CD64, and lysozyme).

Diagnostic criteria for acute myelomonocytic leukemia are [5]:

●≥20 percent monocytes and their precursors

●≥20 percent maturing granulocytic cells

●≥3 percent of blasts positive for MPO (by immunophenotyping or cytochemistry)

Acute monocytic leukemia — This category accounts for 15 percent of AML, NOS [54] and 5 to 10 percent of total AML.

Monoblasts are large with abundant, moderately to intensely basophilic cytoplasm and may demonstrate pseudopod formation, scattered fine azurophilic granules, and vacuoles. Nuclei are round with delicate lacy chromatin and one or more large prominent nucleoli (picture 8). Promonocytes are large with less basophilic cytoplasm with occasional large azurophilic granules and vacuoles. The nucleus is irregular with a delicately convoluted configuration (picture 9 and picture 10) [59].

Diagnostic criteria for acute monocytic leukemia are [5]:

●≥80 percent monocytes and/or their precursors (monoblasts and/or promonocytes)

●≤20 percent maturing granulocytic cells

●Blasts and promonocytes expressing ≥2 monocytic markers, including CD11c, CD14, CD36 and CD64, or NSE positivity on cytochemistry

Almost all cases express HLA-DR, and myeloid antigens are variably expressed, but at least two markers of monocytic differentiation are expressed.

Acute erythroid leukemia — Acute erythroid leukemia (AEL; previously called pure erythroid leukemia, erythroleukemia, or Di Guglielmo's disease) accounts for <1 percent of AML, NOS (picture 11).

AEL is a distinct subtype characterized by neoplastic proliferation of erythroid cells with features of maturation arrest and high prevalence of biallelic TP53 alterations. AEL is characterized by erythroid predominance, which usually constitutes ≥80 percent of bone marrow elements (of which ≥30 percent are proerythroblasts or pronormoblasts). Myeloblasts are <20 percent of all nucleated cells. The erythroblasts react with antibodies to hemoglobin A and glycophorin, and may express CD117, but do not express myeloid markers and do not stain with MPO. In some cases, nucleated erythroid cells constitute <80 percent of bone marrow cellularity; such cases share the same clinicopathologic features of other AEL [60,61].

Diagnostic criteria for AEL are [5]:

●≥30 percent immature erythroid cells (proerythroblasts)

●Bone marrow with erythroid predominance, usually ≥80 percent of cellularity

Acute megakaryoblastic leukemia — Acute megakaryoblastic leukemia (AMKL), which exhibits maturation in the megakaryocytic lineage, accounts for <1 percent of cases of newly diagnosed AML [54].

Morphologically, megakaryoblasts are medium to large and have irregular or indented nuclei and basophilic cytoplasm with blebs or pseudopod formation. Small and large megakaryocytes may be admixed with blasts. Adults with AMKL have a high incidence of an antecedent hematologic disorder, MDS, and/or prior chemotherapy [62].

Diagnosis requires that blasts express at least one of the following platelet glycoproteins: CD41 (glycoprotein llb), CD61 (glycoprotein llla), or CD42b (glycoprotein lb) [5].

Certain categories of leukemia that resemble AMKL are now considered distinct entities:

●Myeloid leukemia in children with Down syndrome or trisomy 21 is a distinct entity, called myeloid leukemia associated with Down syndrome. (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)

●AMKL in children and infants without Down syndrome or trisomy 21 may be associated with cryptic inversion of chromosome 16 and the CBFA2T3::GLIS2 fusion [63], t(1;22) with RBM15::MRTFA [64], or t(5;11) with NUP98::KDM5A [65]. These are included in the category AML with other defined genetic alterations. (See 'Other genetic abnormalities' above.)

SPECIAL CATEGORIES — Classification of special categories of AML and related disorders differ between the International Consensus Classification (ICC) and World Health Organization 5th edition (WHO5).

Therapy-related AML — Therapy-related AML is diagnosed when AML arises in a patient with prior exposure to cytotoxic agents, ionizing radiation, or immune interventions.

●Classification

•International Consensus Classification – "Therapy-related" is added as a qualifier following a diagnosis of AML, myelodysplastic syndromes/neoplasms (MDS), or MDS/AML.

•World Health Organization 5th edition – Myeloid neoplasms that arise secondary to exposure to cytotoxic therapy are included in the category of secondary myeloid neoplasms (which also includes AML in association with a germline predisposition).

Details of the diagnosis and treatment of therapy-related myeloid malignancies are presented separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Predisposing genetic conditions — AML and related myeloid disorders can be associated with germline or inherited gene variants (mutations) mostly in children, but they can also arise in adults.

Myeloid malignancies in the setting of a germline condition may be in association with platelet disorders and chronic thrombocytopenia, constitutional disorders that affect multiple organ systems, or without associated conditions. Many of the affected genes predispose not only to myeloid malignancies but also to lymphoid malignancies. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

A careful family history is important at the time of diagnosis to identify patients with AML who have a germline predisposition. Recognizing this association enables proper diagnosis and management of AML, screening of related donors for allogeneic hematopoietic cell transplantation (HCT), selection of an appropriate transplant conditioning regimen, and genetic counseling for affected family members. A high index of suspicion of germline mutation is important, especially for younger patients with AML and for those who will be transplanted using related donors.

An underlying germline variant gene or syndrome should be specified as a qualifier after the diagnosis of AML or another hematologic malignancy.

●Classification

•International Consensus classification – Myeloid malignancies in association with a germline predisposition constitute a separate category and are included in one of the following groups [4]:

-Hematologic neoplasms with germline predisposition without a constitutional disorder affecting multiple organ systems

-Hematologic neoplasms with germline predisposition associated with a constitutional platelet disorder

-Hematologic neoplasms with germline predisposition associated with a constitutional disorder affecting multiple organ systems

•World Health Organization 5th edition – Myeloid malignancies in association with a germline predisposition are included in the category secondary myeloid neoplasms (which also includes therapy-related AML) in one of the following groups [5]:

-Myeloid neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction

-Myeloid neoplasms with germline predisposition and pre-existing platelet disorder

-Myeloid neoplasms with germline predisposition and potential organ dysfunction

Myeloid sarcoma — Myeloid sarcoma refers to an extramedullary mass of myeloid blasts that effaces the normal tissue architecture. It may precede, present simultaneously with, or follow a diagnosis of AML in bone marrow/blood, or it can occur in relapse or progression of prior MDS or myeloproliferative neoplasms (MPN). Myeloid sarcoma is sometimes the first site of relapse after allogeneic HCT for a myeloid neoplasm.

●Classification

•International Consensus Classification – Myeloid sarcoma constitutes a subtype of AML in the ICC classification [4].

•World Health Organization 5th edition – Myeloid sarcoma is considered a tissue-based manifestation of AML [5].

●Management – Treatment of patients with myeloid sarcoma without evidence of AML on bone marrow or blood is like that for patients with overt AML. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Myeloid sarcoma'.)

Myeloid proliferations related to Down syndrome — Myeloid proliferations related to Down syndrome include two entities that develop in the setting of trisomy 21 [66]:

●Transient abnormal myelopoiesis – Transient abnormal myelopoiesis (TAM) refers to myeloid proliferation that occurs in 10 to 30 percent of newborns with Down syndrome. The disorder is usually characterized by blasts that arise during fetal development in an individual with trisomy 21 plus acquisition of a somatic mutation of GATA1. TAM is usually diagnosed at or around birth, and most cases resolve within one to two months, although there is a risk of early mortality and subsequent AML, as discussed separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

●Myeloid leukemia associated with Down syndrome – Approximately 20 percent of children with TAM develop myeloid leukemia associated with Down syndrome within the first four years of life. In one-third of cases, myeloid leukemia associated with Down syndrome follows a prodrome of an MDS-like period of chronic cytopenias [67]. Most cases are classified as acute megakaryoblastic leukemia. This is discussed in more detail separately. (See "Acute myeloid leukemia in children and adolescents", section on 'Down syndrome and AML'.)

SUMMARY

●Description – Acute myeloid leukemia (AML) is a heterogeneous category of aggressive myeloid malignancies characterized by an accumulation of myeloid blasts in bone marrow, blood, or other tissues and distinguished by arrested myeloid maturation. Classification of AML has evolved with a greater understanding of causes, cytogenetic and molecular features, prognosis, and management.

●Classification systems – Two classification systems for hematologic malignancies that rely heavily on cytogenetic and molecular features of leukemic blasts were published in 2022. (See 'Classification systems' above.)

Use of either model is acceptable, and they supersede previous classification systems:

•International Consensus Classification of Myeloid Neoplasms and Acute Leukemia (see 'International Consensus Classification' above)

•World Health Organization 5th edition (WHO5) myeloid and histiocytic/dendritic neoplasms (see 'World Health Organization 5th edition' above)

These models have many similarities, but they use different systems for classification of AML, and they differ regarding certain diagnostic criteria and labels for AML subtypes.

●Comparison of classification systems – Both International Consensus Classification (ICC) and World Health Organization 5th edition (WHO5) rely heavily on genetic features of AML, and they share many aspects of organization for cases with defining genetic abnormalities. They differ substantially in how they define, categorize, and label cases of AML that lack such defining genetic features and in cases that arise after prior cytotoxic therapy or in association with predisposing germline (inherited) gene variants. (See 'Comparison of International Consensus Classification and World Health Organization 5th edition' above.)

●AML with defining genetic abnormalities – Most cases of AML have a defining genetic abnormality. Examples include:

•Acute promyelocytic leukemia with t(15;17)/PML::RARA (see 'Acute promyelocytic leukemia with PML::RARA' above)

•t(8;21)/RUNX1::RUNX1T1 (see 't(8;21)/RUNX1::RUNX1T1' above)

•inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 (see 'inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::B-MYH11' above)

•t(9;11)(p21.3;q23.3); MLLT3-KMT2A (see 't(9;11)(p21.3;q23.3); MLLT3::KMT2A' above)

•inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM (see 'inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM' above)

•BCR::ABL1 (see 'BCR::ABL1' above)

•Mutated NPM1 (see 'Mutated NPM1' above)

•Mutated CEBPA (see 'Mutated CEBPA' above)

•Mutated TP53 (see 'Mutated TP53' above)

•Myelodysplasia-related gene mutations (see 'Myelodysplasia-related gene mutations' above)

•Myelodysplasia-related cytogenetic abnormalities (see 'Myelodysplasia-related cytogenetic abnormalities' above)

●Other AML subtypes – ICC and WHO5 differ in how they classify AML without a defining genetic abnormality.

•Other International Consensus Classification subtypes – Most such cases are AML, not otherwise specified.

•Other World Health Organization 5th edition subtypes – Cases without a defining genetic feature are classified according to differentiation of blasts.

●Special categories – ICC and WHO5 differ in how they categorize and label the following:

•Therapy related (see 'Therapy-related AML' above)

•Predisposing genetic conditions (see 'Predisposing genetic conditions' above)

•Myeloid sarcoma (see 'Myeloid sarcoma' above)

•Myeloid proliferations related to Down syndrome (see 'Myeloid proliferations related to Down syndrome' above)

ACKNOWLEDGMENT — UpToDate acknowledges John Anastasi, MD, who contributed to earlier versions of this topic review.