Chronic Myelomonocytic Leukemia (CMML) is a rare blood cancer that begins in the bone marrow’s blood-forming cells and causes an overproduction of white blood cells called monocytes. CMML is unique because it has features of two different blood disorders: myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). This means the bone marrow produces too many cells (proliferative), but the cells are abnormal and do not function correctly (dysplastic). The condition affects older adults, with an average diagnosis age between 65 and 75.
Symptoms and Risk Factors
The signs of CMML can be subtle and develop slowly, with some individuals showing no symptoms at diagnosis. When symptoms appear, they often include persistent fatigue, weakness, and shortness of breath due to anemia (a low red blood cell count). Other common experiences are frequent infections from a low number of healthy white blood cells, and easy bruising or bleeding from a shortage of platelets. A feeling of fullness or discomfort in the abdomen can result from an enlarged spleen, where excess monocytes accumulate.
Unexplained weight loss, fever, night sweats, and bone pain are also associated with CMML. While the primary risk factors are not fully understood, several have been identified. Advanced age is the most prominent risk factor, with most cases diagnosed in individuals over 60. The disease is more common in men than in women. Previous exposure to certain industrial chemicals, radiation, or chemotherapy can also increase a person’s risk.
How CMML is Diagnosed
Diagnosing CMML involves a series of medical tests on the blood and bone marrow, often starting when a routine blood test reveals abnormalities. A complete blood count (CBC) measures the different cells in the blood; in CMML, it will show a persistently high number of monocytes, a condition called monocytosis. A peripheral blood smear, where a drop of blood is examined under a microscope, allows specialists to look at the physical appearance of the cells for any irregularities.
A bone marrow aspiration and biopsy are necessary for a definitive diagnosis. This procedure involves taking small samples of bone marrow fluid and tissue from the hip bone for laboratory analysis. Pathologists examine these samples for features of CMML, such as an increased number of monocytes and abnormal-looking (dysplastic) cells. The percentage of immature cells, or blasts, is also counted, which helps in staging the disease.
Genetic testing is another part of the diagnostic process. Tests like cytogenetics and molecular sequencing are used to look for specific changes in the chromosomes or gene mutations of the cancer cells. More than 95% of people with CMML have somatic mutations in genes like TET2, SRSF2, and ASXL1. These genetic markers help confirm the diagnosis, distinguish CMML from other blood disorders, and provide information about the disease’s likely behavior.
CMML Subtypes and Prognosis
After a CMML diagnosis is confirmed, the disease is classified into subtypes to help predict its course and guide treatment decisions. The World Health Organization (WHO) classifies CMML based on the percentage of immature cells, called blasts, found in the blood and bone marrow. CMML-1 is diagnosed when blasts make up less than 5% of the cells in the blood and less than 10% in the bone marrow. CMML-2 is diagnosed when blast percentages are higher, ranging from 5-19% in the blood or 10-19% in the bone marrow.
A patient’s prognosis depends on more than just the subtype. Clinicians use prognostic scoring systems, such as the CMML-specific Prognostic Scoring System (CPSS), to create a more detailed outlook. These models integrate several factors beyond the blast count to assess risk, including specific blood count levels and whether a patient requires red blood cell transfusions.
The presence of specific gene mutations also plays a role in determining prognosis. For instance, mutations in genes like ASXL1, NRAS, RUNX1, and SETBP1 are associated with a poorer outlook. Conversely, the absence of an ASXL1 mutation combined with a TET2 mutation is considered a more favorable genetic profile. By combining all these factors, doctors can better estimate the risk of the disease progressing into acute myeloid leukemia (AML), which occurs in about 15-30% of cases.
Treatment Options for CMML
Treatment for CMML is highly individualized and depends on the disease subtype, risk score, symptoms, and the patient’s overall health. Not everyone requires immediate treatment. For individuals with low-risk CMML who are not experiencing symptoms, a strategy of active monitoring, or “watchful waiting,” may be employed. This involves regular check-ups and blood tests to monitor the disease’s progression.
For patients who have symptoms, supportive care is a primary component of management. This approach aims to alleviate symptoms and includes blood and platelet transfusions, antibiotics to treat or prevent infections, and growth factors to encourage the bone marrow to produce more healthy blood cells. The medication hydroxyurea is often used to lower very high monocyte counts and can help reduce the size of an enlarged spleen.
For higher-risk CMML, disease-modifying therapies are used. Hypomethylating agents (HMAs), such as azacitidine and decitabine, are chemotherapy drugs that can help control the disease. The only potentially curative treatment for CMML is an allogeneic stem cell transplant, where a patient receives healthy blood-forming stem cells from a donor. This is an intensive procedure reserved for a select group of younger, healthier patients with high-risk disease and a suitable donor.