Chronic myelomonocytic leukemia (CMML) is a rare blood cancer originating in the bone marrow, the tissue responsible for making blood cells. The World Health Organization (WHO) classifies CMML as a mixed myelodysplastic/myeloproliferative neoplasm, meaning it exhibits characteristics of two different types of blood disorders. It primarily affects older adults, typically between 68 and 75 years old, and is observed more frequently in men than in women.
Defining Chronic Myelomonocytic Leukemia
CMML is a disorder of hematopoietic stem cells, which are the precursor cells in the bone marrow that develop into all mature blood cells. The disease is characterized by a failure in the normal maturation process alongside an overproduction of a specific type of white blood cell called monocytes. These abnormal monocytes accumulate in the bone marrow and circulate in high numbers in the blood, interfering with the production of healthy red blood cells, platelets, and other white blood cells.
The unique classification of CMML as a mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN) reflects its dual nature. Myelodysplastic features involve the production of abnormal-looking, dysfunctional blood cells and a tendency toward low blood counts (cytopenias) in red cells and platelets. Conversely, myeloproliferative features involve the overgrowth and excessive production of white blood cells, particularly monocytes. This cellular imbalance, stemming from genetic errors, ultimately defines CMML.
Identifying CMML
The initial discovery of CMML often occurs through routine blood work, as the condition may not cause noticeable symptoms in its early stages. When symptoms do appear, they are typically non-specific and develop gradually, often related to the low counts of healthy blood cells. Common presenting complaints include persistent fatigue or weakness due to anemia, frequent or severe infections caused by a lack of functional white blood cells, and easy bruising or bleeding resulting from low platelet counts.
Patients may also experience systemic symptoms like unexplained weight loss, fever, or night sweats, known as B symptoms. An enlarged spleen (splenomegaly) or liver (hepatomegaly) is another physical sign, as the abnormal monocytes can accumulate in these organs. These signs prompt a complete blood count (CBC) test, which is often the first indication of the disease due to the characteristic finding of sustained monocytosis.
Diagnosis requires meeting specific criteria, including a peripheral blood monocyte count of at least 1,000/µL sustained for more than three months, and monocytes must account for at least 10% of the white blood cell count. Other conditions that can cause monocytosis, such as chronic infections, must be excluded. A bone marrow aspiration and biopsy is subsequently performed to confirm the presence of dysplasia in the blood cell lines and to count the percentage of immature cells, called blasts.
Genetic and molecular testing is also performed on the bone marrow sample to look for mutations commonly associated with CMML, which help confirm the diagnosis and provide prognostic information. Frequent mutations are found in genes involved in epigenetic regulation and RNA splicing, such as TET2, ASXL1, and SRSF2. The presence of these specific genetic alterations supports the diagnosis and helps distinguish CMML from other similar blood cancers.
Classification and Disease Progression
CMML is sub-classified based on the percentage of blasts found in the blood and bone marrow, which directly impacts the risk of disease progression. The World Health Organization (WHO) system divides CMML into two main stages: CMML-1 and CMML-2. CMML-1 is defined by a blast percentage of less than 5% in the peripheral blood and less than 10% in the bone marrow.
CMML-2 is a higher-risk stage, defined by having 5% to 19% blasts in the peripheral blood or 10% to 19% blasts in the bone marrow. A blast percentage of 20% or more automatically reclassifies the disease as Acute Myeloid Leukemia (AML). This progression to AML is the most serious complication of CMML, occurring in approximately 15% to 30% of patients over several years.
Beyond the blast count, CMML is also separated into dysplastic and proliferative subtypes based on the total white blood cell (WBC) count. The dysplastic subtype is defined by a WBC count below 13,000/µL and tends to present more like a myelodysplastic syndrome with low blood counts. The proliferative subtype, with a WBC count of 13,000/µL or higher, is associated with a higher risk of developing AML and often presents with an enlarged spleen and systemic symptoms.
Prognostic scoring systems, such as the CMML-specific Prognostic Scoring System (CPSS), integrate multiple factors to assess a patient’s outlook and the likelihood of transformation to AML. These systems consider the percentage of blasts, the presence of specific genetic mutations like ASXL1, and blood count parameters like hemoglobin and platelet levels. This detailed risk assessment helps determine the appropriate management path for each patient.
Current Management Strategies
The management of CMML is highly individualized and depends significantly on the patient’s overall health, age, and the disease’s risk classification determined by prognostic scores. For patients classified as lower-risk or those who are asymptomatic, a strategy of “watchful waiting” may be adopted. This involves close monitoring with regular blood tests and physical examinations, and treatment is initiated only if symptoms worsen or blood counts significantly decline.
For patients with higher-risk disease or those experiencing significant symptoms, drug therapies are employed to manage the condition. Hypomethylating agents (HMAs), such as azacitidine, are a cornerstone of treatment and work by altering the DNA of the abnormal blood cells. These agents aim to reduce the percentage of blasts, improve blood counts, and delay the progression of CMML to AML.
Supportive care is an ongoing aspect of management, focused on alleviating symptoms and improving quality of life. This includes red blood cell and platelet transfusions to address anemia and bleeding issues. Growth factors may also be administered to stimulate the production of healthy blood cells and mitigate low counts.
The only potentially curative treatment for CMML is allogeneic hematopoietic stem cell transplantation, often called a bone marrow transplant. This procedure involves replacing the patient’s diseased stem cells with healthy ones from a donor. Due to the intensity and potential risks of transplantation, it is usually reserved for younger, fitter patients with high-risk disease who have a suitable donor.