Chronic myelomonocytic leukemia (CMML) 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).
According to the WHO classification 2017, CMML is one of the myelodysplastic/myeloproliferative neoplasms.
- persistent peripheral blood monocytosis (≥1x109/L)
- Monocytes accounting for ≥10% of the leukocytes
- WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, primary myelofibrosis, polycythemia vera and essential thrombocythemia are not met
- No rearrangement of PDGFRA, PDGFRB or FGFR1 and no PCM1-JAK2
- Blast constitute < 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
If myelodysplasia is absent or minimal, criteria 1-4 are met and:
- An acquired, clonal cytogenetic or molecular genetic abnormality is present in hematopoietic cells
- The monocytosis has persisted for > 3 months and all other causes of monocytosis (e.g. malignancy, infection, and inflammation) have been excluded.
(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)
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):
<2% blasts in the blood and <5% blasts in bone marrow, no Auer rods
2-4% blasts in the blood or 5-9% blasts in bone marrow, no Auer rods
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
Characteristic for CMML is a peripheral blood monocytosis with a monocyte count ≥1x109/L, it is usually 2-5x109/L, but can also exceed >80x109/L. Depending on the total leukocyte count, CMML is divided into two variants: the so-called dysplastic form (total leukocyte count <13x109/L) and the proliferative form (total leukocyte count ≥13x109/L).
In general, the monocytes are mature and have unremarkable morphology, but they can exhibit unusual nuclear segmentation or chromatin patterns and abnormal granulation. The proportion of promonocytes and (mono-) blasts together must be less than 20%. Dysgranulopoiesis is present in most cases. Cytochemical staining is strongly recommended, especially myeloperoxidase and in particular the unspecific esterase, for assessing the monocytic components.
Immunophenotyping is helpful to distinguish CMML from benign reactive monocytosis. It has been shown that a proportion of ≥94% of so-called classical monocytes (MO1: CD14+, CD16-) in peripheral blood with a specificity and sensitivity of more than 90% each distinguishes a CMML from reactive monocytosis (Selimoglu-Buet et al. 2015). The information obtained by immunophenotyping can also be used to track minimal residual disease under therapy.
Chromosome analysis should be performed in the presence of CMML. Chromosomal changes are present in 20-40% of all cases (Swerdlow et al. 2017). The aberration rate is higher for blasts in the sense of CMML-2 (Such et al. 2011). In most scoring systems (see Prognosis of CMML) chromosomal aberrations play a decisive role, so that chromosomal analysis is required to assess the prognosis here. Common cytogenetic changes are trisomy 8, monosomy 7 or 7q deletion, loss of the Y chromosome, 20q deletion or trisomy 21. A complex aberrant karyotype (defined as at least three aberrations) has been described in 3-6% of cases (Valent et al. 2019). However, these aberrations are not specific for CMML, but are also observed in other - mainly myeloid - haematological neoplasms.
In addition to chromosome analysis or with regard to individual typical alterations, FISH can be performed on interphases or for further clarification of the karyotype on metaphases. On its own, this method is not necessary for the diagnosis or prognosis of CMML. FISH can make a contribution to follow-up examinations and the determination of residual disease after therapy. In addition, FISH can detect cytogenetic cryptic changes (TET2 deletion, NF1 deletion, ETV6 deletion), which are present in 2-10% of cases (Valent et al. 2019).
Since the majority of patients have a normal karyotype, extensive studies have been carried out in recent years to investigate the molecular basis of CMML. In these studies it could be shown that more than 90% of CMML patients have at least one molecular mutation, some of which has prognostic relevance (Patnaik et al. 2018). Table 1 summarises common mutations.
Encoding an epigenetic regulator. TET2 is mutated in about 60% of all CMML patients and is therefore the most frequently mutated gene in CMML.
Affecting the splicing machinery, splicing of pre-mRNA. SRSF2 mutations are present in about 50% of CMML patients.
Encoding a chromatin binding protein and thus also plays a role in epigenetic modifications (histone modification). Mutations in this gene occur with an incidence of about 40%. ASXL1 mutations are associated with a poor prognosis, shorter survival and transformation to AML (Gelsi-Boyer et al. 2010).
Encoding a transcription factor. Mutations in this gene often lead to a differentiation stop, depending on the type of mutation. RUNX1 mutations occur in about 15% of CMML patients
Both NRAS and KRAS, two cytoplasmic proteins of the RAS signalling pathway, can carry activating mutations. NRAS and KRAS mutations are found in approximately 15% and 10% of CMML patients, respectively.
Coding for SET-binding protein 1, for which mutations have recently been detected in various MDS/MPN overlap entities. In CMML patients, SETBP1 mutations are found in approximately 15% of CMML patients, respectively.
Other rarer gene mutations in CMML are with an incidence of about 1-20%: BCOR, CBL, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, NF1, NPM1 and genes of the spliceosome (SF3B1, U2AF1, ZRSR2) (Yoshida et al. 2011, Patnaik et al. 2018). The analysis of these and the more frequently mutated genes listed in Table 1 by means of NGS is recommended by the EHA/ELN (Itzykson et al. 2018).
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 aberrations
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).
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)
|Genetic risk group||Score|
*Cytogenetic risk groups are defined according to Such et al: low, normal, and isolated –Y; intermediate, other abnormalities; and high, trisomy 8, complex karyotype (≥3 abnormalities), and abnormalities of chromosome 7.
In addition to the genetic risk group thus determined, the calculation of the CPSS mole takes into account the proportion of blasts in the bone marrow, leucocytes and transfusion dependency.
Dinmohamed AG et al. The use of medical claims to assess incidence, diagnostic procedures and initial treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia in the Netherlands. Leuk Res. 2015;39(2):177-182.
Elena C et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 2016;128(10):1408-1417.
Gelsi-Boyer V et al. ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010;151(4):365-375.
Germing U et al. Problems in the classification of CMML--dysplastic versus proliferative type. Leuk Res. 1998;22(10):871-878.
Itzykson R et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013;31(19):2428-2436.
Itzykson R et al. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet. Hemasphere 2018;2(6):e150.
Meggendorfer M et al. SRSF2 mutations in 275 patients with chronic myelomonocytic leukemia (CMML). Blood 2012;120(15):3080-3088.
Patnaik MM et al. Chronic Myelomonocytic Leukemia: 2018 Update on Diagnosis, Risk Stratification and Management. Am J Hematol. 2018;93(6):824–840.
Selimoglu-Buet D et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood 2015;125(23):3618-3626.
Such E et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011;96(3):375-383.
Such E et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 2013;121(15):3005-3015.
Swerdlow SH et al. WHO classification of tumours of haematopoetic and lymphoid tissue. International Agency of Research on Cancer 2017; 4. überarbeitete Version.
Valent P et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica 2019;104(10):1935-1949.
Yoshida K et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011;478(7367):64-69.