This entity includes AML with balanced translocation/ inversions, as well as AML with gene mutations, and accounts for about 20–30% of patients with AML. AML with balanced translocations include t(8;21)(q22;q22.1); RUNX1-RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11, PML-RARA, t(9;11)(p21.3;q23.3); KMT2A-MLLT3, t(6;9) (p23;q34.1); DEK-NUP214; inv(3)(q21.3q26.2) or t(3;3)(q21.3; q26.2); GATA2, MECOM, t(1;22)(p13.3;q13.1); RBM15-MKL1; and (provisional entity) AML with BCR-ABL1. Many of these disease categories have characteristic morphological and immunophenotypic features. Of these categories, if PML-RARA and inv(16)(p13.1q22) or t(16;16) are present with t(8;21), AML can be diagnosed regardless of the blast count [3]. AML with BCR-ABL1 is a newly introduced provisional entity that was included separately despite low incidence because its characteristics are different from the blast phase of chronic myeloid leukemia [4] and is an aggressive disease. Moreover, studies have shown that patients with this form of AML might benefit from tyrosine kinase therapy [5, 6].

AML with gene mutations is another category under AML with recurrent genetic abnormalities. AML with mutated NPM1 and biallelic CEBPA have been incorporated into the “AML with recurrent genetic abnormalities” entity, and AML with RUNX1 mutation was added as a new provisional entity. AML with NPM1 mutation is the most recurrent genetic mutation in AML and is usually associated with a normal karyotype [7]. NPM1-mutated AML shows good prognosis, but accompanying FLT3-ITD mutations may alter the prognosis [8, 9]. In the revised classification, only those with biallelic CEBPA mutation are included as a separate entity owing to its beneficial effect on prognosis [10, 11]. AML with mutated RUNX1 has been incorporated in to the AML classification and is known to have poor prognosis [12, 13]. However, a diagnosis of RUNX1-mutated AML should not be made for cases that fulfil the criteria for other specific AML subtypes, including AML-MRC, t-MN, or AML with recurrent genetic abnormalities. Most RUNX1 mutations are monoallelic, and the mutations are commonly frameshift or missense without any hotspots [14]. Although AML with FLT3 mutations are frequently present, it is not separately assigned as an entity due to its presence in many AML subtypes. Nevertheless, owing to their therapeutic [15] and prognostic significance [16], testing for FLT3 mutations must be carried out in all patients with AML [8, 9].

The diagnosis of AML-MRC requires that the following criteria are met. First, the blast count in blood or marrow should be ≥20%; second, patients should have a history of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN), or MDS-related cytogenetic abnormality (Table 2) or multilineage dysplasia; and third, patients should not have received prior cytotoxic or radiation therapy for an unrelated disease or have the recurrent cytogenetic abnormalities described for AML with recurrent genetic abnormalities. AML-MRC generally has a poor prognosis with a lower rate of complete remission than other AML subtypes [17, 18]. To diagnose AML-MRC based on morphology, dysplasia must be present in ≥50% of cells in at least two hematopoietic cell lines. Moreover, multilineage dysplasia alone is insufficient to diagnose AML-MRC in a de novo case of AML with mutated NPM1 or biallelic mutations of CEBPA, as the prognosis is not different regardless of the presence of multilineage dysplasia in these subtypes [19, 20]. Deletion (9q) has been removed from the MDS-related cytogenetic abnormalities that are now used to define AML-MRC owing to the association with NPM1 or biallelic CEBPA mutations [21, 22].

t-MN includes t-AML, t-MDS, t-MDS/MPN, which occur as a complication of cytotoxic therapy and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder. Cytotoxic agents implicated in t-MN include alkylating agents, topoisomerase II inhibitors, some antimetabolites, anti-tubulin agents, and radiation therapy. t-MN accounts for 10–20% of all cases of MDS and AML [23]. Regardless of the blast count and morphologic diagnosis, t-MDS and t-AML are included as t-MN, owing to the presence of prior iatrogenic exposure to mutagenic agents and its relation to pathogenesis of the t-MN, although recent studies have suggested some inherited risk factors [24, 25]. The prognosis of t-MN is generally poor, influenced by cytogenetic and genetic mutations, as well as the underlying malignancy for which prior therapy was received [26, 27].

Cases of AML that are not classified into any of the abovementioned categories are classified as AML, NOS. This category classifies AML based on morphology, cytochemistry, and immunophenotype, which was the basis for earlier AML classifications [1, 2]. Subcategories include AML with minimal differentiation, without maturation, with maturation, acute myelomonocytic leukemia, acute monoblastic and monocytic leukemia, pure erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, and acute panmyelosis with myelofibrosis. Changes have been made for erythroid leukemia and bone marrow with >80% immature erythroid precursors; bone marrow nucleated cells with >30% proerythroblasts is only included in the pure erythroid leukemia category and thus, the myeloblast counts are <20% [28]. Cases previously classified as erythroleukemia (myeloid/erythroid) are now classified as MDS according to the blast count, cytopenia, and dysplasia, because they share greater similarity with MDS than with AML [29, 30].

A tumor mass consisting of myeloid blasts, occurring at a site other than the bone marrow, is diagnosed as myeloid sarcoma. The diagnosis is equivalent to a diagnosis of AML and can precede or coincide with AML [31, 32]. Myeloid sarcoma shows blastic-type as well as monoblastic or myelomonocytic type [31]; recent studies using next-generation sequencing have identified mutations similar to those implicated in AML, such as KIT or FLT3 mutations [33].

Individuals with DS are known to have increased risk of leukemia [34, 35]. Transient abnormal myelopoiesis (TAM) associated with DS and myeloid leukemia associated with DS are included in this category. TAM is a disorder of newborns with DS that presents with clinical and morphological findings of AML at 3–7 days after birth [36]. Most patients exhibit spontaneous remission but others develop AML after 1–3 years. Most cases of myeloid leukemia associated with DS are acute megakaryoblastic leukemia [37]. In individuals with DS, the distinction between MDS and AML is irrelevant; thus, both are included in the category of myeloid leukemia associated with DS. In addition to trisomy 21, mutations of GATA1 are pathognomonic of this category [38]. These children should be treated based on DS-specific protocols [39].