Advertisement

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia

Daniel A. Arber, Attilio Orazi, Robert Hasserjian, Jürgen Thiele, Michael J. Borowitz, Michelle M. Le Beau, Clara D. Bloomfield, Mario Cazzola and James W. Vardiman
This article has an Erratum 128(3):462

Data supplements

Article Figures & Data

Tables

  • Table 1

    WHO classification of myeloid neoplasms and acute leukemia

    WHO myeloid neoplasm and acute leukemia classification
    Myeloproliferative neoplasms (MPN)
     Chronic myeloid leukemia (CML), BCR-ABL1+
     Chronic neutrophilic leukemia (CNL)
     Polycythemia vera (PV)
     Primary myelofibrosis (PMF)
      PMF, prefibrotic/early stage
      PMF, overt fibrotic stage
     Essential thrombocythemia (ET)
     Chronic eosinophilic leukemia, not otherwise specified (NOS)
     MPN, unclassifiable
    Mastocytosis
    Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2
     Myeloid/lymphoid neoplasms with PDGFRA rearrangement
     Myeloid/lymphoid neoplasms with PDGFRB rearrangement
     Myeloid/lymphoid neoplasms with FGFR1 rearrangement
    Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2
    Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
     Chronic myelomonocytic leukemia (CMML)
     Atypical chronic myeloid leukemia (aCML), BCR-ABL1
     Juvenile myelomonocytic leukemia (JMML)
     MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
     MDS/MPN, unclassifiable
    Myelodysplastic syndromes (MDS)
     MDS with single lineage dysplasia
     MDS with ring sideroblasts (MDS-RS)
      MDS-RS and single lineage dysplasia
      MDS-RS and multilineage dysplasia
     MDS with multilineage dysplasia
     MDS with excess blasts
     MDS with isolated del(5q)
     MDS, unclassifiable
    Provisional entity: Refractory cytopenia of childhood
    Myeloid neoplasms with germ line predisposition
    Acute myeloid leukemia (AML) and related neoplasms
     AML with recurrent genetic abnormalities
      AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1
      AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11
      APL with PML-RARA
      AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A
      AML with t(6;9)(p23;q34.1);DEK-NUP214
      AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
      AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1
      Provisional entity: AML with BCR-ABL1
      AML with mutated NPM1
      AML with biallelic mutations of CEBPA
      Provisional entity: AML with mutated RUNX1
     AML with myelodysplasia-related changes
     Therapy-related myeloid neoplasms
     AML, NOS
      AML with minimal differentiation
      AML without maturation
      AML with maturation
      Acute myelomonocytic leukemia
      Acute monoblastic/monocytic leukemia
      Pure erythroid leukemia
      Acute megakaryoblastic leukemia
      Acute basophilic leukemia
      Acute panmyelosis with myelofibrosis
     Myeloid sarcoma
     Myeloid proliferations related to Down syndrome
      Transient abnormal myelopoiesis (TAM)
      Myeloid leukemia associated with Down syndrome
    Blastic plasmacytoid dendritic cell neoplasm
    Acute leukemias of ambiguous lineage
     Acute undifferentiated leukemia
     Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
     MPAL with t(v;11q23.3); KMT2A rearranged
     MPAL, B/myeloid, NOS
     MPAL, T/myeloid, NOS
    B-lymphoblastic leukemia/lymphoma
     B-lymphoblastic leukemia/lymphoma, NOS
     B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
     B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1
     B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged
     B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1
     B-lymphoblastic leukemia/lymphoma with hyperdiploidy
     B-lymphoblastic leukemia/lymphoma with hypodiploidy
     B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH
     B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1
    Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like
    Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21
    T-lymphoblastic leukemia/lymphoma
    Provisional entity: Early T-cell precursor lymphoblastic leukemia
    Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma
  • Table 2

    Criteria for CML, accelerated phase

    CML, accelerated phase criteria
    Any 1 or more of the following hematologic/cytogenetic criteria or response-to-TKI criteria:
    • Persistent or increasing WBC (>10 × 109/L), unresponsive to therapy“Provisional” response-to-TKI criteria
    • Persistent or increasing splenomegaly, unresponsive to therapy• Hematologic resistance to the first TKI (or failure to achieve a complete hematologic response* to the first TKI) or
    • Persistent thrombocytosis (>1000 × 109/L), unresponsive to therapy• Any hematological, cytogenetic, or molecular indications of resistance to 2 sequential TKIs or
    • Persistent thrombocytopenia (<100 × 109/L) unrelated to therapy• Occurrence of 2 or more mutations in BCR-ABL1 during TKI therapy
    • 20% or more basophils in the PB
    • 10%-19% blasts in the PB and/or BM
    • Additional clonal chromosomal abnormalities in Ph+ cells at diagnosis that include “major route” abnormalities (second Ph, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype, or abnormalities of 3q26.2
    • Any new clonal chromosomal abnormality in Ph+ cells that occurs during therapy
    • Large clusters or sheets of small, abnormal megakaryocytes, associated with marked reticulin or collagen fibrosis in biopsy specimens may be considered as presumptive evidence of AP, although these findings are usually associated with 1 or more of the criteria listed above.

    • * Complete hematologic response: WBC, <10 × 109/L; platelet count, <450 × 109/L, no immature granulocytes in the differential, and spleen nonpalpable.

    • The finding of bona fide lymphoblasts in the blood or marrow, even if <10%, should prompt concern that lymphoblastic transformation may be imminent and warrants further clinical and genetic investigation; 20% or more blasts in blood or BM, or an infiltrative proliferation of blasts in an extramedullary site is CML, blast phase.

  • Table 3

    Diagnostic criteria for CNL

    CNL diagnostic criteria
    1. PB WBC ≥25 × 109/L
     Segmented neutrophils plus band forms ≥80% of WBCs
     Neutrophil precursors (promyelocytes, myelocytes, and metamyelocytes) <10% of WBC
     Myeloblasts rarely observed
     Monocyte count <1 × 109/L
     No dysgranulopoiesis
    2. Hypercellular BM
     Neutrophil granulocytes increased in percentage and number
     Neutrophil maturation appears normal
     Myeloblasts <5% of nucleated cells
    3. Not meeting WHO criteria for BCR-ABL1+ CML, PV, ET, or PMF
    4. No rearrangement of PDGFRA, PDGFRB, or FGFR1, or PCM1-JAK2
    5. Presence of CSF3R T618I or other activating CSF3R mutation
    or
    In the absence of a CSFR3R mutation, persistent neutrophilia (at least 3 mo), splenomegaly and no identifiable cause of reactive neutrophilia including absence of a plasma cell neoplasm or, if present, demonstration of clonality of myeloid cells by cytogenetic or molecular studies
  • Table 4

    WHO criteria for PV

    WHO PV criteria
    Major criteria
    1. Hemoglobin >16.5 g/dL in men
    Hemoglobin >16.0 g/dL in women
    or,
    Hematocrit >49% in men
    Hematocrit >48% in women
    or,
    increased red cell mass (RCM)*
    2. BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
    3. Presence of JAK2V617F or JAK2 exon 12 mutation
    Minor criterion
     Subnormal serum erythropoietin level
    Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion
    • * More than 25% above mean normal predicted value.

    • Criterion number 2 (BM biopsy) may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels >18.5 g/dL in men (hematocrit, 55.5%) or >16.5 g/dL in women (hematocrit, 49.5%) if major criterion 3 and the minor criterion are present. However, initial myelofibrosis (present in up to 20% of patients) can only be detected by performing a BM biopsy; this finding may predict a more rapid progression to overt myelofibrosis (post-PV MF).

  • Table 5

    WHO criteria for ET

    WHO ET criteria
    Major criteria
     1. Platelet count ≥450 × 109/L
     2. BM biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers
     3. Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms
     4. Presence of JAK2, CALR, or MPL mutation
    Minor criterion
     Presence of a clonal marker or absence of evidence for reactive thrombocytosis
    Diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion
  • Table 6

    WHO criteria for prePMF

    WHO prePMF criteria
    Major criteria
     1. Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1*, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis
     2. Not meeting the WHO criteria for BCR-ABL1+ CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms
     3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of minor reactive BM reticulin fibrosis
    Minor criteria
    Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
     a. Anemia not attributed to a comorbid condition
     b. Leukocytosis ≥11 × 109/L
     c. Palpable splenomegaly
     d. LDH increased to above upper normal limit of institutional reference range
    Diagnosis of prePMF requires meeting all 3 major criteria, and at least 1 minor criterion
    • * See Table 8.

    • In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.

    • Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.

  • Table 7

    WHO criteria for overt PMF

    WHO overt PMF criteria
    Major criteria
     1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3*
     2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid neoplasms
     3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of reactive myelofibrosis
    Minor criteria
    Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
     a. Anemia not attributed to a comorbid condition
     b. Leukocytosis ≥11 × 109/L
     c. Palpable splenomegaly
     d. LDH increased to above upper normal limit of institutional reference range
     e. Leukoerythroblastosis
    Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion
    • * See Table 8.

    • In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.

    • BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.

  • Table 8

    Grading of myelofibrosis

    Myelofibrosis grading
    MF-0Scattered linear reticulin with no intersections (crossovers) corresponding to normal BM
    MF-1Loose network of reticulin with many intersections, especially in perivascular areas
    MF-2Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibers mostly consistent with collagen, and/or focal osteosclerosis*
    MF-3Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick fibers consistent with collagen, usually associated with osteosclerosis*
    • Semiquantitative grading of BM fibrosis (MF) with minor modifications concerning collagen and osteosclerosis. Fiber density should be assessed only in hematopoietic areas.

    • * In grades MF-2 or MF-3 an additional trichrome stain is recommended.

  • Table 9

    WHO classification of mastocytosis

    WHO mastocytosis classification
    1. Cutaneous mastocytosis (CM)
    2. Systemic mastocytosis
     a. Indolent systemic mastocytosis (ISM)*
     b. Smoldering systemic mastocytosis (SSM)*
     c. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN)
     d. Aggressive systemic mastocytosis (ASM)*
     e. Mast cell leukemia (MCL)
    3. Mast cell sarcoma (MCS)
    • * These subtypes require information regarding B and C findings for complete diagnosis,20 all of which may not be available at the time of initial tissue diagnosis.

    • This category is equivalent to the previously described “systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD).” AHNMD and AHN can be used synonymously.

  • Table 10

    Molecular genetic abnormalities in myeloid/lymphoid neoplasms associated with eosinophilia

    DiseasePresentationGeneticsTreatment
    PDGFRAEosinophiliaCryptic deletion at 4q12Respond to TKI
    ↑Serum tryptaseFIP1L1-PDGFRA, at least 66 other partners
    ↑Marrow mast cells
    PDGFRBEosinophiliat(5;12)(q32;p13.2) ETV6-PDGFRB, at least 25 other partnersRespond to TKI
    Monocytosis mimicking CMML
    FGFR1EosinophiliaTranslocations of 8p11.2Poor prognosis; do not respond to TKI
    Often presents with T-ALL or AMLFGFR1-various partners
    PCM1-JAK2Eosinophiliat(8;9)(p22;p24.1) PCM1-JAK2May respond to JAK2 inhibitors
    Rarely presents with T-LBL or B-ALL
    Bone marrow shows left-shifted erythroid predominance and lymphoid aggregates
    • ↑, Increased.

  • Table 11

    Diagnostic criteria for CMML

    CMML diagnostic criteria
    • Persistent PB monocytosis ≥1 × 109/L, with monocytes accounting for ≥10% of the WBC count
    • Not meeting WHO criteria for BCR-ABL1+ CML, PMF, PV, or ET*
    • No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement or PCM1-JAK2 (should be specifically excluded in cases with eosinophilia)
    • <20% blasts in the blood and BM
    • Dysplasia in 1 or more myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML may still be made if the other requirements are met and
    • An acquired clonal cytogenetic or molecular genetic abnormality is present in hemopoietic cells
    or
    • The monocytosis (as previously defined) has persisted for at least 3 mo and
    • All other causes of monocytosis have been excluded
    • * Cases of MPN can be associated with monocytosis or they can develop it during the course of the disease. These cases may simulate CMML. In these rare instances, a previous documented history of MPN excludes CMML, whereas the presence of MPN features in the BM and/or of MPN-associated mutations (JAK2, CALR, or MPL) tend to support MPN with monocytosis rather than CMML.

    • Blasts and blast equivalents include myeloblasts, monoblasts, and promonocytes. Promonocytes are monocytic precursors with abundant light gray or slightly basophilic cytoplasm with a few scattered, fine lilac-colored granules, finely distributed, stippled nuclear chromatin, variably prominent nucleoli, and delicate nuclear folding or creasing. Abnormal monocytes, which can be present both in the PB and BM, are excluded from the blast count.

    • The presence of mutations in genes often associated with CMML (eg, TET2, SRSF2, ASXL1, SETBP1) in the proper clinical contest can be used to support a diagnosis. It should be noted however, that many of these mutations can be age-related or be present in subclones. Therefore, caution would have to be used in the interpretation of these genetic results.

  • Table 12

    Diagnostic criteria for aCML, BCR-ABL1

    aCML diagnostic criteria
    • PB leukocytosis due to increased numbers of neutrophils and their precursors (promyelocytes, myelocytes, metamyelocytes) comprising ≥10% of leukocytes)
    • Dysgranulopoiesis, which may include abnormal chromatin clumping
    • No or minimal absolute basophilia; basophils usually <2% of leukocytes
    • No or minimal absolute monocytosis; monocytes <10% of leukocytes
    • Hypercellular BM with granulocytic proliferation and granulocytic dysplasia, with or without dysplasia in the erythroid and megakaryocytic lineages
    • <20% blasts in the blood and BM
    • No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement, or PCM1-JAK2
    • Not meeting WHO criteria for BCR-ABL1+ CML, PMF, PV, or ET*
    • * Cases of MPN, particularly those in accelerated phase and/or in post-polycythemic or post-essential thrombocythemic myelofibrosis, if neutrophilic, may simulate aCML. A previous history of MPN, the presence of MPN features in the BM and/or MPN-associated mutations (in JAK2, CALR, or MPL) tend to exclude a diagnosis of aCML. Conversely, a diagnosis of aCML is supported by the presence of SETBP1 and/or ETNK1 mutations. The presence of a CSF3R mutation is uncommon in aCML and if detected should prompt a careful morphologic review to exclude an alternative diagnosis of CNL or other myeloid neoplasm.

  • Table 13

    Diagnostic criteria for MDS/MPN with ring sideroblasts and thrombocytosis

    MDS/MPN diagnostic criteria
    • Anemia associated with erythroid lineage dysplasia with or without multilineage dysplasia, ≥15% ring sideroblasts,* <1% blasts in PB and <5% blasts in the BM
    • Persistent thrombocytosis with platelet count ≥450 × 109/L
    • Presence of a SF3B1 mutation or, in the absence of SF3B1 mutation, no history of recent cytotoxic or growth factor therapy that could explain the myelodysplastic/myeloproliferative features
    • No BCR-ABL1 fusion gene, no rearrangement of PDGFRA, PDGFRB, or FGFR1; or PCM1-JAK2; no (3;3)(q21;q26), inv(3)(q21q26) or del(5q)
    • No preceding history of MPN, MDS (except MDS-RS), or other type of MDS/MPN
    • * At least 15% ring sideroblasts required even if SF3B1 mutation is detected.

    • A diagnosis of MDS/MPN-RS-T is strongly supported by the presence of SF3B1 mutation together with a mutation in JAK2 V617F, CALR, or MPL genes.

    • In a case which otherwise fulfills the diagnostic criteria for MDS with isolated del(5q)-no or minimal absolute basophilia; basophils usually <2% of leukocytes.

  • Table 14

    Diagnostic criteria for JMML

    JMML diagnostic criteria
    I. Clinical and hematologic features (all 4 features mandatory)
     • PB monocyte count ≥1 × 109/L
     • Blast percentage in PB and BM <20%
     • Splenomegaly
     • Absence of Philadelphia chromosome (BCR/ABL1 rearrangement)
    II. Genetic studies (1 finding sufficient)
     • Somatic mutation in PTPN11* or KRAS* or NRAS*
     • Clinical diagnosis of NF1 or NF1 mutation
     • Germ line CBL mutation and loss of heterozygosity of CBL
    III. For patients without genetic features, besides the clinical and hematologic features listed under I, the following criteria must be fulfilled:
     • Monosomy 7 or any other chromosomal abnormality or at least 2 of the following criteria:
      • Hemoglobin F increased for age
      • Myeloid or erythroid precursors on PB smear
      • GM-CSF hypersensitivity in colony assay
      • Hyperphosphorylation of STAT5
    • Modified from Locatelli and Niemeyer25 with permission.

    • * Germ line mutations (indicating Noonan syndrome) need to be excluded.

    • Occasional cases with heterozygous splice site mutations.

  • Table 15

    PB and BM findings and cytogenetics of MDS

    NameDysplastic lineagesCytopenias*Ring sideroblasts as % of marrow erythroid elementsBM and PB blastsCytogenetics by conventional karyotype analysis
    MDS with single lineage dysplasia (MDS-SLD)11 or 2<15%/<5%BM <5%, PB <1%, no Auer rodsAny, unless fulfills all criteria for MDS with isolated del(5q)
    MDS with multilineage dysplasia (MDS-MLD)2 or 31-3<15%/<5%BM <5%, PB <1%, no Auer rodsAny, unless fulfills all criteria for MDS with isolated del(5q)
    MDS with ring sideroblasts (MDS-RS)
     MDS-RS with single lineage dysplasia (MDS-RS-SLD)11 or 2≥15%/≥5%BM <5%, PB <1%, no Auer rodsAny, unless fulfills all criteria for MDS with isolated del(5q)
     MDS-RS with multilineage dysplasia (MDS-RS-MLD)2 or 31-3≥15%/≥5%BM <5%, PB <1%, no Auer rodsAny, unless fulfills all criteria for MDS with isolated del(5q)
    MDS with isolated del(5q)1-31-2None or anyBM <5%, PB <1%, no Auer rodsdel(5q) alone or with 1 additional abnormality except −7 or del(7q)
    MDS with excess blasts (MDS-EB)
     MDS-EB-10-31-3None or anyBM 5%-9% or PB 2%-4%, no Auer rodsAny
     MDS-EB-20-31-3None or anyBM 10%-19% or PB 5%-19% or Auer rodsAny
    MDS, unclassifiable (MDS-U)
     with 1% blood blasts1-31-3None or anyBM <5%, PB = 1%, no Auer rodsAny
     with single lineage dysplasia and pancytopenia13None or anyBM <5%, PB <1%, no Auer rodsAny
     based on defining cytogenetic abnormality01-3<15%§BM <5%, PB <1%, no Auer rodsMDS-defining abnormality
    Refractory cytopenia of childhood1-31-3NoneBM <5%, PB <2%Any
    • * Cytopenias defined as: hemoglobin, <10 g/dL; platelet count, <100 × 109/L; and absolute neutrophil count, <1.8 × 109/L. Rarely, MDS may present with mild anemia or thrombocytopenia above these levels. PB monocytes must be <1 × 109/L

    • If SF3B1 mutation is present.

    • One percent PB blasts must be recorded on at least 2 separate occasions.

    • § Cases with ≥15% ring sideroblasts by definition have significant erythroid dysplasia, and are classified as MDS-RS-SLD.

  • Table 16

    Diagnostic approach to myeloid neoplasms when erythroid precursors comprise ≥50% of BM nucleated cells

    BM erythroid precursorsMyeloblast % of all cells in BM (or PB)Prior therapy?Recurring WHO genetic abnormality?Meets criteria for AML-MRC?Fourth edition diagnosisUpdated fourth edition diagnosis
    ≥50%NAYesNANATherapy-related myeloid neoplasmTherapy-related myeloid neoplasm
    ≥50%≥20%NoYesNAAML with recurring genetic abnormalityAML with recurring genetic abnormality
    ≥50%≥20%NoNoYesAML with myelodysplasia-related changesAML with myelodysplasia-related changes
    ≥50%≥20%NoNoNoAML, NOS, acute erythroid leukemia (erythroid/myeloid type)AML, NOS (non erythroid subtype)
    ≥50%<20%, but ≥20% of nonerythroid cellsNoNo*NAAML, NOS, acute erythroid leukemia (erythroid/myeloid subtype)MDS
    ≥50%<20%, and <20% of nonerythroid cellsNoNo*NAMDSMDS
    >80% immature erythroid precursors with ≥30% proerythroblasts<20%NoNo*NAAML, NOS, acute erythroid leukemia (pure erythroid type)AML, NOS, acute erythroid leukemia (pure erythroid type)
    • AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; NA, not applicable.

    • * Cases of AML t(8;21)(q22;q22.1);RUNX1-RUNX1T1, AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 or APL with PML-RARA, may rarely occur in this setting with <20% blasts and those diagnoses would take precedence over a diagnosis of AML, NOS, or MDS.

    • Classify based on myeloblast percentage of all BM cells and of PB leukocytes and other MDS criteria.

  • Table 17

    Classification of myeloid neoplasms with germ line predisposition

    Myeloid neoplasm classification
    Myeloid neoplasms with germ line predisposition without a preexisting disorder or organ dysfunction
     AML with germ line CEBPA mutation
     Myeloid neoplasms with germ line DDX41 mutation*
    Myeloid neoplasms with germ line predisposition and preexisting platelet disorders
     Myeloid neoplasms with germ line RUNX1 mutation*
     Myeloid neoplasms with germ line ANKRD26 mutation*
     Myeloid neoplasms with germ line ETV6 mutation*
    Myeloid neoplasms with germ line predisposition and other organ dysfunction
     Myeloid neoplasms with germ line GATA2 mutation
     Myeloid neoplasms associated with BM failure syndromes
     Myeloid neoplasms associated with telomere biology disorders
     JMML associated with neurofibromatosis, Noonan syndrome or
     Noonan syndrome-like disorders
     Myeloid neoplasms associated with Down syndrome*
    • * Lymphoid neoplasms also reported.

  • Table 18

    Cytogenetic abnormalities sufficient to diagnose AML with myelodysplasia-related changes when ≥20% PB or BM blasts are present and prior therapy has been excluded

    Cytogenetic abnormalities
    Complex karyotype (3 or more abnormalities)
    Unbalanced abnormalities
     −7/del(7q)
     del(5q)/t(5q)
     i(17q)/t(17p)
     −13/del(13q)
     del(11q)
     del(12p)/t(12p)
     idic(X)(q13)
    Balanced abnormalities
     t(11;16)(q23.3;p13.3)
     t(3;21)(q26.2;q22.1)
     t(1;3)(p36.3;q21.2)
     t(2;11)(p21;q23.3)
     t(5;12)(q32;p13.2)
     t(5;7)(q32;q11.2)
     t(5;17)(q32;p13.2)
     t(5;10)(q32;q21.2)
     t(3;5)(q25.3;q35.1)
  • Table 19

    Criteria for lineage assignment for a diagnosis of MPAL

    Lineage assignment criteria
    Myeloid lineage
     MPO* (flow cytometry, immunohistochemistry, or cytochemistry)
     or
     Monocytic differentiation (at least 2 of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
    T-lineage
     Strong cytoplasmic CD3 (with antibodies to CD3 ε chain)
     or
     Surface CD3
    B-lineage
     Strong CD19 with at least 1 of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10
     or
     Weak CD19 with at least 2 of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10
    • * See “Acute leukemias of ambiguous lineage” for caveats related to weaker antigen expression, or to expression by immunohistochemistry only.

    • Strong defined as equal or brighter than the normal B or T cells in the sample.