Other less frequent signs and symptoms consist of anaemia, fever, weight loss, night sweats, infection, bleeding, synovitis, lymphadenopathy, skin rashes, pleural effusion, pericardial effusion and peritoneal effusion. Cause
Although the cause of CMML is unknown, environmental carcinogens, ionising radiation and cytotoxic agents may have a role in causing disease. Approximately one third of cases of MDS with a monocyte count of >10% and <1x109/L will progress to CMML. Pathogenesis
With a high rate of Ras mutation in CMML, deregulation of this signalling pathway has been linked to the pathogenesis of the disease. Tumour necrosis factor, GM-CSF, interleukin-3, interleukin-4, interleukin-6, and interleukin-10 may have a role in hyperproliferative CMML cells. These cytokines can stimulate the growth of CMML in vitro. Hypermethylation of cytosine residues (usually in the promoter regions of genes) occurs in many malignancies to regulate gene expression. One commonly hypermethylated gene in CMML is p15INK4b, a gene involved in cell cycle regulation. Genetic mutations
Clonal genetic abnormalities are common in CMML but they are not specific for diagnosis of the disease. The most common found are the 8+, −7/del (7q) and structural 12p abnormalities. KRAS and NRAS are mutated in 25–40% of the cases of CMML. The Jak2 V617F mutation is found in 10% of cases. Mutations in transcription factors such as RUNX1, CEBPA, NPM1 and WT1 have been found in up to 30% of cases. Mutations of CBL are found in approximately 5–18% of cases. Mutations in the TET2 gene are found in approximately 40–50% of CMML.
Some cytogenetic abnormalities have implications on the prognosis of CMML. Normal karyotypes or the single loss of the Y chromosome have low risk prognoses. Trisomy 8, chromosome 7 abnormalities and complex karyotypes comprise a high risk group. Other cytogenetic abnormalities have intermediate prognoses. Somatic mutations in genes such as ASXL1 and EZH2 are associated with a poor prognosis.CMML has a 20–30% chance of transformation to AML, a lower rate than other similar diseases. The CMML-2 subtype is associated with increased risk of transformation and ASXL1 and RUNX1 mutations also increase the risk of transition to AML. Scoring systems
IPSS
The International Prognostic Scoring System (IPSS) was developed in the mid-1990s to assess the prognosis of MDS patients. This system stratifies cases into 2 groups; a lower-risk group (sub divided into low and intermediate-1) and a higher risk (subdivided into intermediate-2 and high). It uses the blast percentage, number of cytopenias and bone marrow cytogenetics data to place cases of CMML into these groups. Due to the scoring system being developed for MDS, the more myeloproliferative cases of CMML (WBC >13x109) are excluded from the scoring system. Although the IPSS scoring system is used clinically, there is a high variability in each group. For this reason, new modalities for assessing prognosis in MDS (and CMML) are being developed. MD Anderson Prognostic Scoring System
A new method developed using data from the M.D.