Chronic myelomonocytic
leukemia (CMML)

  • 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:
  • Recommendation:
    no
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

CMML (chronic myelomonocytic leukemia) is a clonal hematopoietic malignancy with features of both a myeloproliferative neoplasm (MNP) and a myelodysplastic syndrome (MDS). The incidence of CMML is about 0.4/100,000 per year, with the highest incidence of about 4/100,000 in the group of >80 years of age (Dinmohamed et al. 2015). The median age of onset of the disease is 70-72 years (Germing et al. 1998).

CMML - Classification

According to the WHO classification 2017, CMML is one of the myelodysplastic/myeloproliferative neoplasms.


Diagnostic criteria

  • persistent peripheral blood monocytosis (≥1x109/L)
  • Monocytes accounting for ≥10% of the leukocytes
  • No rearrangement of PDGFRA, PDGFRB or FGFR1 and no PCM1-JAK2
  • Blast count < 20% of the cells in the peripheral blood and bone marrow
  • Dysplasia involving > 1 myeloid lineages classically dysplasia in one or more myeloid lines or
  • WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, primary myelofibrosis, polycythemia vera and essential thrombocythemia are not met

If there is no dysplasia or only minimal dysplasia but the other criteria for CMML are fulfilled, CMML can be diagnosed in the presence of an acquired clonal cytogenetic or molecular genetic alteration or if monocytosis has persisted for at least three months and all other possible causes (e.g. malignancy, infection, inflammation) have been ruled out (Swerdlow et al. 2017).

The detection of an acquired cytogenetic or molecular genetic alteration thus represents a diagnostic criterion according to WHO 2017. The presence of mutations in genes such as TET2, SRSF2, ASXL1 or SETPB1, which are often associated with CMML, can support the diagnosis of CMML in a suitable clinical context. However, mutations in these genes may also be age-associated (clonal haematopoiesis of indeterminate potential, CHIP), so that interpretation in conjunction with the other diagnostic criteria is required.


CMML WHO Classification 2017 (Swerdlow et al. 2017)

Myelodysplastic/myeloproliferative neoplasms

Chronic myelomonocytic leukemia (CMML)

Furthermore, the CMML is subdivided into three categories, defined by the percentage of blasts and promonocytes in the peripheral blood and bone marrow (Swerdlow et al. 2017):

CMML-0

<2% blasts in the blood and <5% blasts in bone marrow, no Auer rods

CMML-1

2-4% blasts in the blood or 5-9% blasts in bone marrow, no Auer rods

CMML-2

5-19% blasts in the blood, 10-19% blasts in bone marrow or Auer rods are present; < 20% blasts in the bone marrow and blood

in more than

90%

of patients with NGS (Next Generation Sequencing) one or more mutations are found (oncopedia guideline CMML)

Diagnostics of CMML

Prognosis of CMML

The median survival time of patients with CMML is 20-40 months, 15-30% of patients show progression to AML (Swerdlow et al. 2017).

For mutations in the genes ASXL1, NRAS, RUNX1 and SETBP1 a prognostically unfavourable significance was proven, which is taken into account in the calculation of the prognosis score according to Elena et al. (2016) (see below). A prognostically negative influence was also shown for SRSF2 mutations (Itzykson et al. 2013), which, however, could not be demonstrated in another study (Meggendorfer et al. 2012). For TET2 mutations no negative effect on survival could be shown (Meggendorfer et al. 2012; Itzykson et al. 2013).


Prognostic scoring systems for the risk classification of patients

According to Such et al (2011), CMML can be divided cytogenetically into three prognostic groups.

  • Favourable: normal karyotype or loss of the Y chromosome; approx. in 80% of all patients

  • Adverse: Trisomy 8, aberrations affecting chromosome 7 or complex aberrant karyotype (≥ 3 aberrations)

  • Intermediary: all other abnormalities

Based on this cytogenetic risk classification as well as the parameters CMML subtype according to WHO and FAB and transfusion dependence, the CPSS score according to Such et al (2013) is calculated.

The scoring system according to Itzykson et al. (2013) includes for risk classification purposes not only age, leucocytes, platelets and anemia but also a molecular genetic mutation, namely the ASXL1 mutation status (see Table 2). With these parameters a patient can be classified into the prognostic groups favourable (0-4 points), intermediate (5-7 points) and unfavourable (8-12 points).

Table 2: Prognostic scoring system

according to Itzykson et al. (2013)
Prognostic variableScoring points

Age > 65 Years

2

WBC > 15x109/L

3

Anemia
(hemoglobin <10g/dL in women and < 11g/dL in men)

2

Platelets < 100x109/L

2

ASXL1 mutated

2

With the scoring system according to Elena et al. (2016), CMML patients are classified into different risk groups by means of cyto- and molecular genetic parameters. Based on the cytogenetic risk classification according to Such et al. (2011) and the detection of mutations in ASXL1, NRAS, RUNX1 and/or SETBP1, a patient can be prognostically classified into the groups favourable (0 points), intermediate-1 (1 point), intermediate-2 (2 points) or unfavourable (≥3 points) (see Table 3).

Table 3: Prognostic scoring system (genetic risk group)

according to Elena et al (2016)
Scoring points

0

1

2

Cytogenetic risk group according to Such et al. (2011)

favourable

intermediate

poor

Gene mutations

 

ASXL1 mutation

RUNX1 mutation

 

NRAS mutation

 

 

SETBP1 mutation

 

In addition to the genetic risk group thus determined, the calculation of the CPSS mol takes into account the proportion of blasts in the bone marrow, leucocytes and transfusion dependency.


Calculation of prognosis

Here you can access the prognosis calculation of the CPSS-Mol-Score.

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