Acute Myeloid Leukemia: Classification

WHO classification of acute myeloid leukemia/myeloid neoplasms.

AML with specific cytogenetic or molecular genetic features.
  • AML with t(8;21)(q22;22), molecular: AML1/ETO
  • Acute promyelocytic leukemia with t(15;17)(q22;q11-12), PML / RAR-α.
  • AML with abnormal bone markosinophils (inv(16)(p13q22) or t(16;16)(p13;q11), CBFβ/MYH11).
  • AML with t(9;11)(p22;q23) (MLLT3-MLL) aberration.
  • AML with t(6;9)(p23;q34);(DEK-NUP214)
  • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2);(RPN1-EVI1)
  • AML (megakaryoblastic) with t(1;22)(p13;q13);(RBM15-MKL1)
  • Provisional: AML with NPM1 mutation.
  • Provisional: AML with CEBPA mutation
AML with myelodysplasia-associated changes(AML-MDS-related).
  • With a history of myelodysplasia (medical history).
  • MDS-typical cytogenetic changes.
  • Multiline dysplasia
Therapy-associated AML and MDS
  • After alkylating agents
  • After epipodophyllotoxins
  • After ionizing radiation
  • Other types
AML, not elsewhere classified
  • AML with minimal differentiation (formerly M0).
  • AML without maturation (formerly M1).
  • AML with maturation (formerly M2)
  • Acute myelomonocytic leukemia (formerly M4).
  • Acute monoblastic/monocytic leukemia (formerly M5).
  • Acute erythroleukemia, type A, B (formerly M6).
  • Acute megakaryocytic leukemia (formerly M7).
  • Acute basophilic leukemia
  • Acute panmyelosis with myelofibrosis
Myelosarcoma
  • Extramedullary manifestation of AML (manifestation of AML outside the bone marrow).
Acute leukemia without definite lineage affiliation
  • Undifferentiated acute leukemia
  • Bilinear acute leukemia
  • Biphenotypic acute leukemia
AML associated with trisomy 21 (Down syndrome).
Blastic plasmocytoid dendritic cell neoplasia
  • Extremely rare entity with skin infiltrates, lesions.

Scientists propose a classification of AML into eleven subtypes (genome classification), to which 81% of all leukemias could be assigned in the study. The most common variant, accounting for 27%, is characterized by mutations in the gene NPM1. This mutation is already considered by the current WHO classification (see above). Further mutations (in the genes DNMT3A, IDH1, IDH2 and TET2) will be considered with the newly proposed classification, which have not been considered in the WHO classification so far. The new classification is expected to provide better prognostic predictions for patients. Furthermore, for example, targeted therapy with FLT3 inhibitors or Ras inhibitors could be applied to tumors in the FLT3 or RAS gene. European LeukemiaNet classification (ELN classification) of AML risk groups (by former and current).

Risk group Cytogenetic and molecular genetic characteristics.
Favorable
  • T(8;21)(q22;q22); RUNX1-RUNX1T1
  • Inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
  • NPM1 mutation without FLT3-ITD (normal karyotype) or with FLT3-ITDlow* .
  • CEBPA mutation (normal karyotype).
Intermediary
  • Mutant NPM1 with FLT3-ITDhigh* (normal karyotype).
  • Wild-type NPM1 without FLT3-ITD (normal karyotype) or with FLT3-ITDlow* (with or without unfavorable genetic aberrations).
  • T(9;11)(p22;q23); MLLT3-KMT2A§
  • Cytogenetic aberrations that were not classified as favorable or unfavorable.
Unfavorable
  • T(6;9)(p23;q34); DEK-NUP214
  • T(v;11)(v;q23); KMT2A gene rearrangement.
  • T(9;22)(q34.1;q11.2); BCR-ABL1
  • Inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2, MECOM (EVI1).
  • -5 or del(5q); -7; -17/abnl(17p)
  • Complex karyotype (≥3 aberrations†).
  • Monosomal karyotype (a monosomy associated with at least one other monosomy or other structural chromosomal aberration (other than CBF-AML)).
  • Wild-type NPM1 with FLT3-ITDhigh* .
  • Mutant RUNX1‡
  • Mutated ASXL1‡
  • Mutated TP53

Legend

  • * FLT3-ITDlow = mutant-wild-type allele quotient <0.5; FLT3-ITDhigh = mutant-wild-type allele quotient ≥0.5. Determined via semiquantitative measurement of FLT3-ITD allele quotient by DNA fragment analysis as the quotient of the AUC for FLT3-ITD divided by the AUC for FLT3-wild-type.
  • § in the presence of rarer aberrations classified as unfavorable, the t(9;11) “stings,” i.e., it tips the scales for classification into the intermediate risk group
  • † only applicable if one of the WHO-defined AML-typical aberrations is not simultaneously present (i.e., t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1).
  • ‡ to be classified as unfavorable only in the absence of aberrations classified as favorable, i.e., in the presence of favorable alterations, these tip the balance toward classification in the favorable risk group

FAB classification (French-American-British)

According to the FAB classification, AML is divided into eight subtypes M0-M7 based on morphologic and cytochemical characteristics of leukemic blasts. Individual subtypes are associated with typical cytogenetic alterations:

FAB subtype Description Morphology Auer- rods MPO UE Cytogenetic aberrations* Frequency
M0 AML with minimal differentiation Myeloblasts without granules – -* * – < 5 %
M1 AML without maturation Myeloblasts +/- granules +/- + – t(9;22) 15-20 %
M2 AML with maturation Myeloblasts with granules, single myelocytes + + – t(8;21) 25-30 %
M3 Acute promyelocytic leukemia (APL) Promyelocytes, distinctly granular ++ + – t(15;17) 5-10 %
M4 Acute myelomonocytic leukemia Myeloblasts and promyelocytes > 20%. +/- + + inv/del(16) for M4eo 20-30 %
M5a Acute monocyte leukemia without maturation large monoblasts – – + t/del(11) 5 %
M5b Acute monocyte leukemia with maturation. Monoblasts, promonocytes, and monocytes; monocytosis in peripheral blood. – – + t(8;16) 5-10 %
M6 Acute erythroleukemia Megaloblastic erythropoiesis > 50%, myeloblasts > 30%. + + +/- 5 %
M7 Acute megakaryoblastic leukemia Megakaryoblasts – – +/- 5 %

Legend

  • MPO: myeloperoxidase
  • UE: nonspecific esterase

* Only most common abberations* * immunologically detectable.