BCR-ABL1-negative myeloproliferative neoplasms (MPN) - overview

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

Myeloproliferative neoplasms (MPNs) are rare, clonal diseases of the hematopoietic stem cell that share many common features, which is why they are often difficult to distinguish from one another, especially in the early stages, and can also merge in individual cases. The annual incidence of all MPN subtypes combined is approximately 6/100,000 (Swerdlow et al. 2017). MPNs usually affect people of older age with a median of 60-65 years (Barbui 2012). Characteristic of MPN is hypercellularity of the bone marrow, specifically the myeloid cell series, and increased numbers of erythrocytes, granulocytes, and/or platelets in the peripheral blood, depending on the entity (Haferlach et al. 2008, Swerdlow et al. 2017).

MPNs are basically divided into chronic myeloid leukemia (CML) as BCR-ABL1-positive MPNs and BCR-ABL1-negative myeloproliferative neoplasms (Haferlach et al. 2008, Swerdlow et al. 2017).

Classification of MPN

The classification into BCR-ABL1-positive CML and BCR-ABL1-negative myeloproliferative neoplasms is according to the WHO classification (see Table 1) (Swerdlow et al. 2017).

Table 1: MPN WHO classification 2017.

(Swerdlow et al., 2017)

Myeloproliferative Neoplasms (MPN)

Chronic myeloid leukemia (CML)

BCR-ABL1 positive

Chronic neutrophilic leukemia (CNL)

BCR-ABL1 negative

Polyzythemia vera (PV)

Primary myelofibrosis (PMF)

  • prefibrotic stage
  • Overt fibrotic stage

Essential thrombocythemia (ET)

Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS)

MPN, unclassifiable (MPN-U)

The three entities polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are often also grouped under the term "classic" BCR-ABL1-negative MPN. Primary myelofibrosis was also previously referred to as osteomyelofibrosis (OMF) or chronic idiopathic myelofibrosis (CIMF).

In contrast to CML, which is clearly defined by the presence of a BCR-ABL1 rearrangement or a Philadelphia chromosome, BCR-ABL1-negative myeloproliferative disorders are a very heterogeneous group of diseases from a cytogenetic and molecular genetic perspective. This is mainly reflected in the frequency and nature of clonal chromosomal abnormalities as well as molecular genetic abnormalities.

MPN: Diagnostics

MPN: Prognosis

In addition to increased age, leukocytosis, and thrombosis (Gangat et al. 2011, Barbui et al. 2018), in general, the detection of chromosomal abnormalities at diagnosis of an MPN seems to be associated with a less favorable prognosis. The presence of complex karyotypes during the course of an MPN increases the likelihood of transition to blast crisis (Haferlach et al. 2008). SNP array analyses showed clustered deletions of the genes ETV6 (Chr. 12), TP53 (Chr. 17), or RUNX1 (Chr. 21) in blast crisis (Thoennissen et al. 2010).


Gene mutations influence the risk profile of "classic" BCR-ABL1-negative MPN

The JAK2 V617F mutation is the most common mutation in MPN. PV is almost always associated with this mutation (97%). In addition to the JAK2 V617F mutation, mutations in the CALR (20-25%) and MPL (3-8%) genes often occur in ET and PMF. These mutations are among the driver mutations in MPN, but do not allow a specific diagnosis due to their cross-entity occurrence.

81% of PMF patients, 53% of PV patients, and 53% of ET patients show additional mutations (non-driver mutations) in addition to the driver mutations, including the genes SRSF2, ASXL1, IDH2, EZH2, TP53, U2AF1, CBL, SF3B1 and SH2B3 (see also Fig. 1). IDH2 mutations are classified as a risk factor in all three classic BCR-ABL1-negative MPNs (Tefferi et al. 2016, Tefferi & Vannucchi 2017). Furthermore, each of the three entities has an entity-specific risk profile, an overview is given in Figure 1.

Figure 1: Recurrent non-driver gene mutations in PMF, PV and ET with prognostic impact (adapted from Tefferi et al. 2016, Tefferi & Vannucchi 2017).

Recurrent mutations in PMF patients frequently affect the SRSF2, ASXL1, IDH2, EZH2, TP53, U2AF1, and CBL genes. These gene mutations are prognostically significant and the presence of two or more mutations worsens prognosis (Guglielmelli et al. 2011, Vannucchi et al. 2013, Guglielmelli et al. 2014, Tefferi et al. 2014).

In PV patients, recurrent mutations include SRSF2, ASXL1 and IDH2, each of which is associated with decreased overall survival and myelofibrosis/leukemia-free survival (Tefferi et al. 2016, Tefferi & Vannucchi 2017).

Approximately 15% of ET patients have a mutation in at least one of the IDH2, EZH2, TP53, U2AF1, SF2B1 or SH2B3 genes. These mutations are considered risk factors and are associated with reduced overall survival or myelofibrosis- and leukemia-free survival (Tefferi & Vannucchi 2017).

For a detailed insight into the individual MPNs and their genetic risk profiles, please refer to the infotexts of the respective entity:

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