Classification of acute myeloid leukemia (AML)

INTRODUCTION — Acute myeloid leukemia (AML) refers to a large and diverse category of clinically aggressive hematologic neoplasms that are characterized by accumulation of myeloid blasts in bone marrow, blood, 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 (table 1). Clinically, AML is manifested by 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 also been called acute myelogenous leukemia and acute non-lymphocytic leukemia.

This topic describes the World Health Organization (WHO) classification system for AML [1].

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

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

●(See "Pathogenesis of acute myeloid leukemia".)

●(See "Prognosis of acute myeloid leukemia".)

●(See "Overview of acute myeloid leukemia in adults".)

CLINICAL PRESENTATION AND DIAGNOSIS — AML is typically manifested by 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 bone marrow, blood, or other disease sites by morphology, immunophenotype, chromosome analysis (karyotype), 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".)

CLASSIFICATION SYSTEMS — AML classification systems aid management by organizing these heterogeneous disorders according to biologic and patient characteristics. Although certain categories of AML have prognostic implications, classification schemes differ from prognostic risk stratification models.

We classify AML according to the current World Health Organization (WHO) classification [1,2], supplemented with some familiar features from the French-American-British (FAB) classification scheme [3].

●WHO classification – The WHO classification of AML is based on integration of clinical and laboratory features [1,2], as described below. (See 'Overview of WHO classification' below.)

However, the WHO scheme has limitations, such as not including several key mutations and other features that contribute to pathogenesis or may influence treatment and prognosis. (See 'Limitations' below.)

●FAB classification – The FAB classification was primarily based on clinical features and morphology of leukemic cells [3], was prevalent for decades, and remains familiar to many clinicians. (See 'FAB classification' below.)

●Other AML classification schemes – The WHO and FAB classification schemes differ from prognostic stratification models, such as those developed by the European LeukemiaNet [4] or the United Kingdom Medical Research Council (UKMRC) [5]. The European LeukemiaNet and UKMRC models were constructed according to patient outcomes, in addition to shared biologic features. Prognostic stratification of AML is described separately. (See "Prognosis of acute myeloid leukemia".)

Other classification systems have been proposed that attempt to incorporate gene expression patterns, clustered mutations, and/or epigenetic alterations that are not included in the WHO scheme [6,7]. No such model has yet been clinically validated, broadly accepted, or should be used at present for clinical management of AML.

WHO classification — The 2016 WHO classification is based on integration of clinical features, leukemic cell morphology, immunophenotyping, cytogenetics, and molecular genetics [1,2]. It also recognizes special categories of AML that reflect patient history (eg, therapy-related AML, AML with myelodysplastic syndrome [MDS]-related changes) or anatomic features (ie, myeloid sarcoma). The WHO framework identifies distinct biologic entities with the hope that it will further elucidate molecular pathways, facilitate clinical trials, and optimize treatment of AML (eg, using targeted therapies or other approaches).

Overview of WHO classification — Six main categories of AML are recognized in the current WHO classification [1,2]:

●AML with recurrent genetic abnormalities – This category includes subtypes with characteristic genetic abnormalities. The category is further divided according to whether the molecular abnormalities are associated with:

•Characteristic chromosomal changes (eg, reciprocal chromosomal rearrangements or inversions) – (See 'Defined structural abnormalities' below.)

•No associated karyotypic abnormalities – (See 'AML with gene mutations' below.)

●AML with myelodysplasia-related features – AML with myelodysplasia-related changes (AML-MRC) refers to AML with MDS-related morphologic or karyotypic findings, which lacks genetic features of AML and/or arises in a patient with a history of MDS or MDS/myeloproliferative neoplasm (MPN). (See 'AML with myelodysplasia-related changes' below.)

●Therapy-related AML – Therapy-related AML (t-AML), therapy-related MDS (t-MDS), and therapy-related MDS/MPN are complications of treatment with chemotherapy or radiation previously administered for a malignancy or non-malignant disorder. (See 'Therapy-related AML' below.)

●AML, not otherwise specified (NOS) – This large category includes diverse categories of AML that have recognizable clinical, morphologic, and/or immunophenotypic features, but lack characteristic karyotypic or diagnostic molecular features and do not fulfill criteria for AML-MRC or t-AML. We subdivide AML, NOS according to FAB morphologic and clinical features. (See 'AML not otherwise specified' below.)

●Myeloid sarcoma – This category describes a distinct clinical presentation, rather than a morphologic or genetic subtype of AML. Myeloid sarcoma refers to a tumor mass of myeloid blasts outside of bone marrow that effaces the local tissue architecture. (See 'Myeloid sarcoma' below.)

●Myeloid proliferations related to Down syndrome (DS) – Down syndrome (trisomy 21) is associated with increased risk for AML [8-10]. More than half of cases of DS-associated AML that arise after the neonatal period are acute megakaryoblastic leukemia. (See 'Myeloid proliferations related to Down syndrome' below.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare leukemia arising from the precursors of plasmacytoid dendritic cells, is no longer considered a type of AML; BPDCN is considered a unique category of leukemia in the current WHO classification. (See "Blastic plasmacytoid dendritic cell neoplasm".)

Limitations — The WHO classification of AML is widely used in the management of AML, as its construction is based on decades of experience, it can classify nearly all cases of AML, and it has sufficient flexibility to enable modification as new molecular findings emerge. However, certain limitations of the WHO 2016 scheme should be recognized:

●AML is associated with nearly two dozen recurrent mutations. The Cancer Genome Atlas (TCGA) research network analysis of 200 cases reported an average of 13 mutations per case and nearly all cases of AML had at least one driver mutation [11].

The WHO classification scheme incorporates many, but not all, known mutations that have prognostic significance and/or offer opportunities for targeted therapy. Examples include FLT3 internal tandem duplication (FLT3-ITD) or mutations of KIT or IDH. Furthermore, the WHO system does not account for certain combinations of mutations (eg, NPM1 and FLT3-ITD) that appear to cluster in subtypes of AML.

●As many as one-quarter to one-third of cases of AML are described as AML, NOS, because they are not captured by one of the five other categories of AML [12]. Gene-expression profiling or epigenetic findings are associated with certain AML subtypes [7,13,14], but they are not currently in widespread clinical use. Nevertheless, AML, NOS will likely be further subdivided in future classification schemes, based on genetic, epigenetic, or other features.

●WHO classification does not stratify AML according to prognosis, as do schemes from the European LeukemiaNet [4] and UKMRC [5].

FAB classification — The FAB classification was based on clinical features and blast morphology, supplemented by histochemical staining and recognition of certain non-random chromosomal rearrangements [3]. The FAB classification was widely used for decades and is familiar to many clinicians. The FAB classification distinguished eight categories of AML, but it lacked important karyotypic and genetic features, had only limited prognostic utility, and had little impact on management of AML.

Aspects of the FAB classification were incorporated into the WHO model and can aid in description of cases of AML, NOS. (See 'AML not otherwise specified' below.)

WHO classification — WHO categories of AML are primarily defined by cytogenetic and molecular genetic features, but clinical, morphologic, and/or immunophenotypic features are used in some instances, as described below [15].

AML WITH RECURRENT GENETIC ABNORMALITIES — AML with recurrent genetic abnormalities accounts for 20 to 30 percent of AML cases (table 1) [1].

This category contains the most common AML variants with distinct genetic abnormalities of prognostic significance. There are nine defined structural or molecular abnormalities that define these subtypes of AML; some cases may have chromosomal abnormalities in addition to the defining molecular genetic abnormality.

The World Health Organization (WHO) scheme also includes two provisional entities identified at the molecular level (AML with mutated RUNX1 and AML with BCR-ABL1).

Defined structural abnormalities

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 — The finding of t(8;21)(q22;q22), RUNX1-RUNX1T1 is considered diagnostic for AML, regardless of the blast count in bone marrow or blood [16]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis'.)

AML with t(8;21) identifies a morphologically and clinically distinct subset of AML with the following features [1,2]:

●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) [5]. t(8;21) is the most frequent cytogenetic abnormality in children with AML (12 to 15 percent) [17,18]. Myeloid sarcoma can be present at diagnosis.

●Bone marrow appearance – Promyelocytes, myelocytes, and metamyelocytes are often prominent and abundant. Bone marrow eosinophilia is common.

●Myeloblasts – The large myeloblasts tend to have indented nuclei, abundant basophilic cytoplasm with numerous azurophilic granules, and a prominent paranuclear hof. 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-Huet 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 [19]. This leukemia can co-express lymphoid markers (eg, CD19, PAX5, cytoplasmic CD79) [20-22], 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) [23]. Further description of this translocation is presented separately. (See "Cytogenetic abnormalities in acute myeloid leukemia", section on 't(8;21); RUNX1-RUNX1T1'.)

●Prognosis – This leukemia is associated with a favorable prognosis [24]. 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 [25].

AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 — AML with these abnormalities of chromosome 16 usually exhibit monocytic and granulocytic differentiation with an abnormal eosinophil component. 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) [5]. 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 [26,27].

●Bone marrow appearance – In addition to the typical morphologic features of AML, bone marrow demonstrates abnormalities of eosinophils, including all stages of eosinophilic maturation (ie, no maturation arrest) and immature eosinophilic granules seen in the promyelocyte and myelocyte stages of development [16].  

●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 eosinophilic granules (picture 1).  

●Immunophenotype – The immunophenotype is often complex with multiple blast populations: immature blasts (CD34+, CD117+), and populations that are more granulocytic (CD13+,CD33+, CD15+, CD65+, MPO+) or monocytic (CD14+, CD4+, CD11b+, CD11c, CD64, CD36, 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 "Cytogenetic abnormalities in acute myeloid leukemia", 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 [28].

APL 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 [1]. 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 retinoic acid alone, or in combination with arsenic trioxide. It was previously known as APL with t(15;17)(q24.1;q21.2) (figure 1) and AML-M3.

●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 [5]. Further description of the 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 2). 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.

●Immunophenotype – Hypergranular variants are CD33+, CD64+; have variable CD13; and low expression of HLA-DR, CD34, and leukocyte integrins (CD11a, CD11b, CD18). Microgranular variants have CD34 or CD2 expression on some cells.

●Cytogenetics – Nearly all cases are associated with t(15;17)(q24.1;q21.2), but the current WHO nomenclature recognizes that PML-RARA may also be the result of complex cytogenetic rearrangements [29,30]. (See "Cytogenetic abnormalities in acute myeloid leukemia", section on 't(15;17); PML-RARA'.)

Cases with morphology resembling APL but with variant translocations that are not uniformly responsive to retinoic acid are classified as APL with variant PML-RARA translocations [31,32]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Pathologic features'.)

●Prognosis – There is risk of early death from DIC, but treatment centered on using all-trans retinoic acid (ATRA) and arsenic trioxide is associated with the most favorable prognosis among AML cytogenetic categories. APL represents a medical emergency, but if managed appropriately, it usually has a very favorable outcome.

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

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

●Clinical – t(9;11) is more common in children (9 to 12 percent) than in adults (2 percent) [5,16]. 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 are HL-DR+, CD33+, CD65+, and CD4+, with low expression of myeloid markers (eg, CD13, CD14) [33]. Adult cases express more markers of monocytic differentiation, with variable expression of CD34 and CD117 [34].

●Cytogenetics – t(9;11)(p21.3;q23.3) may be accompanied by secondary cytogenetic abnormalities, such as gain of chromosome 8 [35,36].

KMT2A (previously known as ALL-1, MLL-1) has been involved in >80 different translocations [37]. Further details regarding translocations involving KMT2A are presented separately. (See "Cytogenetic abnormalities in acute myeloid leukemia", 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)(p23;q34.1); DEK-NUP214 — This subtype is associated with 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 [5,38]. Patients may present with pancytopenia and lower white blood cell (WBC) counts than other AML subtypes [39].

●Bone marrow appearance – Bone marrow presents with variable morphology, basophilia, and single or multilineage dysplasia [16,40,41].

●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) [41]. Details of this translocation are presented separately. (See "Cytogenetic abnormalities in acute myeloid leukemia", section on 't(6;9); DEK-NUP214'.)

●Prognosis – AML with t(6;9)(p23;q34); DEK-NUP214 has a poor prognosis [5,16,38,40].

AML with 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.

●Clinical – This subset accounts for 1 to 2 percent of AML [35,42]. Giant, hypogranular platelets are common and bare megakaryocytic nuclei and hypogranular neutrophils with pseudo-Pelger-Huet anomaly may be seen in blood.

●Bone marrow appearance – Megakaryocytes may be dysplastic and increased in number, with non-lobated or bilobed nuclei [43-45]. There may be multilineage dysplasia in non-blast 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 myelodysplastic syndrome (MDS)/AML. (See 'Therapy-related AML' below.)

●Myeloblasts – Blasts may be variable, with little differentiation, myelomonocytic, or megakaryoblastic features.    

●Immunophenotype – Blasts are positive for CD34, CD33, CD13, CD117, and HLA-DR; most express CD38. A subset of cases express 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 [46,47].

A familial form of AML caused by monoallelic mutations in GATA2 is different and 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 [48-51].

AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1 — This subset generally shows maturation in the megakaryocytic lineage.

●Clinical – This rare entity accounts for <0.5 percent of cases of newly diagnosed AML [5,16]. It is typically a megakaryoblastic process occurring in infants. Infants with Down syndrome may develop this leukemia, with or without the mutation [52]. Most patients present with marked hepatosplenomegaly, anemia, thrombocytopenia, and a moderately elevated WBC count [53]. It may present as a mass that resembles a sarcoma.

●Bone marrow appearance – Small and large megakaryocytes may be present that are admixed with blasts.

●Myeloblasts – Morphologically, the megakaryoblasts are medium to large-sized, with irregular or indented nuclei and basophilic cytoplasm with blebs or pseudopod formation. The malignant cells resemble those of acute megakaryoblastic leukemia. (See 'Acute megakaryoblastic leukemia (FAB M7)' below.)

●Immunophenotype – Megakaryoblasts express platelet glycoproteins (eg, CD41, CD42b, CD61) and may express myeloid markers (eg, CD13, CD33).

●Cytogenetics – t(1;22) is present or there is molecular evidence of RBM15-MKL1 fusion.

●Prognosis – This is generally associated with worse prognosis than acute megakaryoblastic leukemia without t(1;22) [52,54-56].

AML with BCR-ABL1 — AML with BCR-ABL1 is included as a provisional entity in the current WHO classification [2].

The Philadelphia chromosome, t(9;22)(q34;q11.2), or its gene product, BCR-ABL1, is found in a small percentage of patients with AML (2 percent), a higher percentage of patients with mixed-phenotype acute leukemia (38 percent), and it has been associated with adverse outcomes [57,58]. On genomic analysis, these cases display some abnormalities also seen in acute lymphoblastic leukemia (ALL) with BCR-ABL1, including deletions in IKZF1 and CDNK1A/B [59]. Unlike chronic myeloid leukemia (CML) at any phase, 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 a distinct entity from CML myeloid blast crisis.

AML with gene mutations — Many patients with AML have well-characterized mutations detectable with molecular techniques, despite a normal karyotype. Molecular characterization should be done at the time of diagnosis because specific targeted therapy is available for some patients (eg, AML with mutations of IDH1, IDH2, or FLT3). (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Bone marrow biopsy and aspirate'.)

AML with mutated NPM1 — The current WHO classification recognizes AML with mutations of the nucleophosmin gene (NPM1) as a subtype of AML with recurrent genetic abnormalities (table 1) [2,53].

●Clinical – NPM1 mutation is found in 2 to 8 percent of childhood AML and 27 to 35 percent of adult AML [60]. Patients often have anemia, thrombocytopenia, and higher WBC counts than other subtypes of AML [61]. There may be extramedullary involvement (eg, gingiva, skin, lymph nodes).

●Bone marrow – Bone marrow is hypercellular and the 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 [62]. Blasts express CD33 and may express CD117, CD123, and CD110 [63].

●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 [1,2,60]. The prognostic impact of NPM1 mutations is discussed in more detail separately. (See "Prognosis of acute myeloid leukemia", section on 'NPM gene'.)

AML with biallelic mutations of CEBPA — The current WHO classification recognizes AML with biallelic mutations of CEBPA as a subtype of AML with recurrent genetic abnormalities (table 1) [1,2]. Most cases exhibit little maturation, but some manifest myelomonocytic or monoblastic features.

●Clinical – Biallelic mutations of CEBPA are present in 4 to 9 percent of children and young adults [64-68]; it is less common in older patients. Patients may present with higher level of hemoglobin and lower platelet counts than other AML [68-70].

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'.)

●Bone marrow – There are no distinctive morphologic features. Most cases exhibit little or no maturation [64,65,69]. Multilineage dysplasia is present in one-quarter of cases [71].

●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 [68,72,73].

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

AML with mutated RUNX1 — The current WHO classification recognizes AML with mutated RUNX1 as a provisional entity (table 1) [2].

Acquired mutations of RUNX1 (located at chromosome 21q22) are found in 10 to 33 percent of persons with de novo MDS and AML [11,74-76]. These patients may have lower WBC counts, hemoglobin, and blast counts than AML without RUNX1 mutation [74,77]. There are no distinctive morphologic features. RUNX1 mutations are generally associated with adverse prognosis.

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 an increased lifetime risk of developing MDS, AML, and T cell ALL. The 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)'.)

AML WITH MYELODYSPLASIA-RELATED CHANGES — AML with myelodysplasia-related features (previously called AML with multilineage dysplasia) (table 1) is defined by cases that fit the criteria for a diagnosis of AML (≥20 percent blasts), without a prior cytotoxic therapy for an unrelated disease, and ≥1 of the following characteristics [78]:

●AML that evolves from previously documented myelodysplastic syndrome (MDS).

●AML with MDS-related cytogenetic abnormalities, such as monosomy 5 or del(5q), monosomy 7 or del(7q), isochromosome 17q (table 2).

●AML with morphologically identified multilineage dysplasia (ie, dysplasia in ≥50 percent of cells in ≥2 hematopoietic lineages). As an exception, patients with NPM1 mutations or biallelic CEBPA mutations and evidence of multilineage dysplasia (MLD) are classified according to those mutations, rather than as AML with MDS-related features.

Examples of dysplastic changes that may be seen in AML with MDS-related features include:

•Dysplastic neutrophils with hypogranular cytoplasm, hyposegmented nuclei (eg, pseudo-Pelger-Huet cells), and/or bizarrely segmented nuclei (picture 3 and picture 4).

•Dysplastic erythrocytes with megaloblastoid changes, karyorrhexis, nuclear irregularity, nuclear fragmentation, multinucleation, ring sideroblasts, cytoplasmic vacuoles, and/or periodic acid-Schiff positivity (picture 5).

•Dysplastic megakaryocytes that are small (ie, micro-megakaryocytes) or normal to large size with non-lobulated or multiple small widely separated nuclei (picture 6).

●AML cannot have cytogenetic abnormalities that define AML with recurrent genetic abnormalities.

Patients with AML who have a prior history of MDS or have MDS-related cytogenetic abnormalities have a poor outcome with conventional therapy. Such patients frequently demonstrate MLD. In contrast, the identification of MLD in the absence of these two features may not predict a poor outcome.

A retrospective analysis of 408 patients with AML with MDS-related features or AML not otherwise specified (AML, NOS) examined the prognostic implication of these three diagnostic features [79]. Patients who had AML with MDS-related features, based solely upon the presence of MLD, had a similar median event-free survival (17 versus 16 months) and similar rates of three-year overall survival (57 versus 55 percent) as patients with AML, NOS. In comparison, MDS-related cytogenetics predicted an inferior outcome.

THERAPY-RELATED AML — The diagnosis of therapy-related myeloid neoplasm (t-MN) is made when blood and bone marrow demonstrates morphologic, immunophenotypic, and cytogenetic changes consistent with the diagnosis of AML, myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm (MPN) in a patient with prior exposure to cytotoxic agents and/or ionizing radiation.

Details on the diagnosis and treatment of t-MN, including t-AML, are presented separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

AML NOT OTHERWISE SPECIFIED — Cases of AML that do not meet the criteria for the categories described above are classified as AML, not otherwise specified (NOS). We subclassify cases of AML, NOS according to the morphologic correspondence with the French-American-British (FAB) classification system (table 1).

AML with minimal differentiation (FAB M0) — This category corresponds to 6 percent of AML, NOS [12].

The leukemic blasts are minimally differentiated, with no cytoplasmic granules or Auer rods, and they cannot be distinguished microscopically from lymphoblasts (picture 7) [80-82]. Blasts are negative for myeloperoxidase (MPO), express antigens of early hematopoiesis (eg, CD34, CD117, and CD33) and myeloid antigens (eg, CD13, CD33, CD117), but lack antigens of more mature myeloid cells (eg, CD14, CD15, CD11b, CD64). Expression of TdT and the T cell antigen CD7 may be present.

AML without maturation (FAB M1) — This category corresponds to 25 percent of AML, NOS [12] and 5 to 10 percent of total AML. Blasts account for >90 percent of total cells. The blasts are large with grayish-blue cytoplasm and large nuclei with prominent nucleoli (picture 8). At least 3 percent of the blasts stain for MPO and some cases contain azurophilic granules and/or Auer rods. Many cases express antigens of early hematopoiesis (eg, CD34, CD38, 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 (FAB M2) — This category accounts for 28 percent of AML, NOS [12] and 10 percent of all AML. Blasts account for <90 percent of the marrow cellularity, and maturation is defined by presence of ≥10 percent of the bone marrow cells showing differentiation to promyelocytes, myelocytes, and/or mature neutrophils. Blasts may or may not have azurophilic granules (picture 9) [53] and/or Auer rods. Blasts may express antigens of early hematopoiesis (eg, CD34, CD38, HLA-DR), myeloid-associated antigens (eg, CD13, CD33), and antigens associated with granulocytic maturation (CD65, CD11b, and CD15). Monocytic markers (eg, CD14, CD64) are usually negative.

Acute myelomonocytic leukemia (FAB M4) — This category accounts for 21 percent of AML, NOS [12] and 5 to 10 percent of all AML (picture 10). This leukemia has ≥20 percent blasts (including promonocytes); neutrophils and their precursors and monocytes and their precursors each account for ≥20 percent of marrow cells [53]. The monocytes can be recognized morphologically, by staining with nonspecific esterase, or by immunophenotype (eg, expression of CD14, CD11c, CD64, and lysozyme).

Acute monoblastic and monocytic leukemia (FAB M5A and M5B) — This category accounts for 15 percent of AML, NOS [12] and 5 to 10 percent of total AML. More than 80 percent of bone marrow cells are of the monocytic lineage (monoblasts, promonocytes, and monocytes) and <20 percent are of the granulocytic lineage [53]. Promonocytes are considered blast equivalents for determining the blast percentage. Auer rods are rare and hemophagocytosis may be present.

●M5A – In monoblastic leukemia (M5A) >80 percent of bone marrow cells are monoblasts. 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 11).

●M5B – In monocytic leukemia (M5B), promonocytes and mature monocytes predominate, but with <80 percent monoblasts. Promonocytes are large with less basophilic and sometimes more obviously granulated cytoplasm with occasional large azurophilic granules and vacuoles. The nucleus is irregular with a delicately convoluted configuration (picture 12 and picture 13) [83].

Almost all cases express HLA-DR, myeloid antigens are variably expressed, and there is usually expression of ≥2 markers of monocytic differentiation (eg, CD14, CD4, CD11b, CD11c, CD64, CD68, CD36, lysozyme).

Pure erythroid leukemia (FAB M6) — Pure erythroid leukemia (acute erythroid leukemia, erythroleukemia, or Di Guglielmo's disease) accounts for <1 percent of AML, NOS (picture 14). To meet the diagnostic criteria for pure erythroid leukemia, >80 percent immature erythroid precursors should be present, with ≥30 percent proerythroblasts [2,53]. Myeloblasts are <20 percent of all nucleated cells. The erythroblasts do not express markers of myeloid lineage and do not stain with MPO [2,84]. They react with antibodies to hemoglobin A and glycophorin and may express CD117.

A diagnosis of pure erythroid leukemia is made only in patients without exposure to cytotoxic agents and without AML-associated recurrent genetic abnormalities.

Acute megakaryoblastic leukemia (FAB M7) — This category accounts for 1 percent of AML, NOS [12]. The bone marrow contains ≥20 percent blasts, at least half of which are of megakaryocyte lineage [85-88]. Megakaryoblasts are distinguished by their resemblance to normal megakaryocytes or by staining for megakaryocytic markers (eg, CD41, CD61) or von Willebrand factor. Megakaryoblasts are medium to large cells with basophilic, often agranular cytoplasm that may have distinct cytoplasmic blebs or pseudopod formation. The nucleus is round, slightly irregular or indented with fine reticular chromatin and one to three nucleoli (picture 15). The megakaryoblasts are consistently negative for MPO. Megakaryoblasts are not equivalent to micro-megakaryocytes, which are dysplastic but mature megakaryocytes.

●Children – Acute megakaryoblastic leukemia in infants and children may be associated with t(1;22) [89] and Down syndrome (trisomy 21) [90]. Those cases associated with Down syndrome are classified separately. (See 'AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1' above and 'Myeloid proliferations related to Down syndrome' below.)

●Adults – Adults with acute megakaryoblastic leukemia have a high incidence of an antecedent hematologic disorder, MDS, and/or prior chemotherapy [87]. Those cases with t(1;22) are classified as AML with recurring genetic abnormalities. (See 'AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1' above.)

Many cases of acute megakaryoblastic leukemia in adults have prominent multilineage dysplasia or MDS-associated cytogenetic changes that might better be classified as AML with MDS-related features. (See 'AML with myelodysplasia-related changes' above.)

Acute basophilic leukemia — This is a very rare category of AML in which the primary differentiation is toward basophils. Circulating blasts contain moderately basophilic cytoplasm with variable numbers of coarse basophilic granules that are positive for metachromatic staining with toluidine blue [1]. Clinically, there may be cutaneous involvement, organomegaly, lytic bone lesions, and/or symptoms related to hyperhistaminemia.

Acute panmyelosis with myelofibrosis — This is a very rare category with an acute panmyeloid proliferation with ≥20 percent blasts in bone marrow or blood that does not fulfil criteria for any other category of AML. Patients are acutely ill with constitutional symptoms and pancytopenia. Bone marrow biopsy with immunohistochemistry is usually required to diagnose this condition, as bone marrow aspirates are often unsuccessful (ie, "dry tap") [1]. The bone marrow is hypercellular with diffusely fibrotic stroma, and increased erythroid and granulocytic precursors and megakaryocytes. Foci of dysplastic blasts and small dysplastic megakaryocytes are commonly found.  

MYELOID SARCOMA — Myeloid sarcoma refers to an extramedullary mass consisting of myeloid blasts, with or without maturation, that effaces the normal tissue architecture [2,91].

Myeloid sarcoma is not a subtype of AML per se, but rather a distinct clinical presentation of any subtype of AML. Myeloid sarcoma may precede bone marrow disease or present simultaneously; it may be seen in relapse or as progression of a prior myelodysplastic syndrome or myeloproliferative neoplasm.

Management of patients with myeloid sarcoma without evidence of AML on bone marrow or blood is similar to 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 — In the current World Health Organization (WHO) classification, myeloid proliferations related to Down syndrome (DS) include two entities that develop in the setting of trisomy 21 [1,2,10]:

●Transient myeloproliferative disorder (TMD) – TMD refers to myeloid proliferation that occurs in 10 to 30 percent of newborns with DS. 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. TMD 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)".)

●AML of DS – Approximately 20 percent of children with TMD develop AML within the first four years of life. In one-third of cases, DS-AML follows a prodrome of myelodysplastic syndrome characterized by chronic cytopenias [92]. 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 of AML – Acute myeloid leukemia (AML) is a diverse collection of aggressive myeloid malignancies that are characterized by accumulation of myeloid blasts in bone marrow, blood, or other tissues and distinguished by arrested myeloid maturation.

●WHO classification – The current World Health Organization (WHO) classification is the preferred system for categorizing AML. The WHO scheme organizes cases of AML by biologic and patient characteristics, including clinical features, leukemic cell morphology, immunophenotyping, cytogenetics, and molecular genetics. Although some WHO categories of AML are associated with outcomes, it is not a prognostic model. (See 'WHO classification' above.)

WHO classification has superseded the French-American-British (FAB) classification, which was based primarily on clinical features and blast morphology. Nevertheless, we find FAB descriptors useful for distinguishing the WHO category of AML, not otherwise specified (NOS).

●Overview of WHO classification – There are six main categories in the WHO 2017 classification of AML:

•AML with recurrent genetic abnormalities – AML with characteristic genetic abnormalities is divided according to those cases with:

-Characteristic chromosomal changes – (See 'Defined structural abnormalities' above.)

-No associated karyotypic abnormalities – (See 'AML with gene mutations' above.)

●AML with myelodysplasia-related features – AML with myelodysplasia-related changes (AML-MRC) refers to AML with myelodysplastic syndrome (MDS)-related morphologic or karyotypic findings that lacks genetic features of AML and/or arises in a patient with a history of MDS or MDS/myeloproliferative neoplasm (MPN). (See 'AML with myelodysplasia-related changes' above.)

●Therapy-related AML – AML that arises after chemotherapy or radiation therapy is described as therapy-related AML (t-AML), therapy-related MDS (t-MDS), or therapy-related MDS/MPN, according to diagnostic criteria for those entities. (See 'Therapy-related AML' above.)

●AML, NOS – This large category includes diverse categories of AML with recognizable clinical, morphologic, and/or immunophenotypic features, which lack characteristic karyotypic or diagnostic molecular features and do not fulfill criteria for AML-MRC or t-AML.

We favor subdividing AML, NOS according to FAB morphologic descriptors. (See 'AML not otherwise specified' above.)

●Myeloid sarcoma – A myeloid sarcoma is a tumor mass of myeloid blasts at a site outside the bone marrow that effaces the local tissue architecture. This category describes a distinct clinical presentation, rather than a morphologic or genetic subtype of AML.

●Myeloid proliferations related to Down syndrome (DS) – DS (trisomy 21) is associated with (see 'Myeloid proliferations related to Down syndrome' above):

•Transient myeloproliferative disorder (TMD) – A disorder of circulating blasts that are present in up to one-third of neonates with DS that spontaneously resolves in most cases.

•DS-associated AML – Most cases of DS-AML are megakaryoblastic.

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