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2016 revision to WHO classification of myelodysplastic/myeloproliferative neoplasms

1 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, while the presence of MPN features in the bone marrow and/or of MPN-associated mutations (JAK2, CALR or MPL) tend to support MPN with monocytosis rather than CMML.

2 Blasts and blast equivalents include myeloblasts, monoblasts and promonocytes. Promonocytes are monocytic precursors with abundant light grey 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.

3 The presence of mutations in genes often associated with CMML (e.g. 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 sub clones. Therefore caution would have to be used in the interpretation of these genetic results.

4 Cases of myeloproliferative neoplasms (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 bone marrow 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 chronic neutrophilic leukemia or other myeloid neoplasm.

5 15% ring sideroblasts required even if SF3B1 mutation is detected.

6 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

7 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.

Disease Peripheral blood findings Bone marrow findings

Chronic myelomonocytic leukemia (CMML)

Peripheral blood monocytosis >1x109/L

Not meeting WHO criteria for BCR/ABL1-positive chronic myeloid leukemia (CML), primary myelofibrosis (PMF), polycythemia vera (PV) or essential thrombocythemia (ET)1

No rearrangement of PDGFRA, PDGFRB or FGFR1

<20% blasts2

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 cells3 OR the monocytosis (as previously defined) has persisted for at least 3 months and all other causes of monocytosis have been excluded.

Dysplasia in one or more myeloid lineage1

<20% blasts2

Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML)

Leukocytosis, neutrophilia

Neutrophilic dysplasia

Neutrophils and their precursors ≥10% of leukocytes

No BCR-ABL1 fusion gene

No evidence of PDGFRA, PDGFRB or FGFR1 rearrangement or PCM1-JAK2 (should be specifically excluded in cases with eosinophilia)

No or minimal basophilia

Monocytes <10% of leukocytes

<20% blasts

Not meeting WHO criteria for PMF, PV or ET4

Hypercellular BM with granulocytic proliferation and granulocytic dysplasia with or without dysplastic erythroid and megakaryocytic lineages

<20% blasts

Juvenile myelomonocytic leukemia (JML)

I. Clinical and hematologic features (all 4 features mandatory):

  • Peripheral blood monocyte count >1x10 9/L
  • Blast percentage in peripheral blood and bone marrow <20%
  • Splenomegaly
  • Absence of Philadelphia chromosome (BCR/ABL1 rearrangement).

II. Genetic studies (1 finding sufficient):

  • Somatic mutation in PTPN11 or KRAS or NRAS (germline mutations - indicating Noonan syndrome - need to be excluded)
  • Clinical diagnosis of NF1 or NF1 mutation
  • Germline CBL mutation and loss of heterozygosity of CBL (occasional cases with heterozygous splice site mutations)

III. For patients without genetic features, besides 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 peripheral blood smear
    • GM-CSF hypersensitivity in colony assay
    • Hyper-phosphorylation of STAT

<20% blasts

Evidence of clonality

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)

Anemia

<1% blasts in PB

Persistent thrombocytosis >450 x 109/L

Presence of SF3B1 mutation or, in the absence of SF3B1 mutation, no history of recent cytotoxic or growth factor therapy that could explain the myelodysplastic/myeloproliferative features6. No BCR-ABL1 fusion gene, no rearrangement of PDGFRA, PDGFRB or FGFR1; or PCM1-JAK2; no t(3;3)(q21;q26),inv(3)(q21q26) or del(5q)7

No preceding MPN, MDS (except MDS-RS), or other type of MDS/MPN

<5% blasts in BM

Dyserythropoiesis with ring sideroblasts ≥15% of erythroid precursors5

Abnormal megakaryocytes as observed in PMF or ET

Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN)

Mixed MDS and MPN features

No prior diagnosis of MDS or MPN

No history of recent growth factor or cytotoxic therapy to explain MDS or MPN features

No BCR-ABL1 fusion gene or rearrangements of PDGFRA or PDGFRB

Mixed MDS and MPN features

<20% blasts