Chronic Myelomonocytic Leukemia (CMML) is a rare cancer originating in the blood-forming stem cells of the bone marrow. It is classified as a leukemia because it involves the uncontrolled growth of abnormal white blood cells. CMML is specifically characterized by a persistent and excessive number of monocytes circulating in the blood. Although considered chronic, CMML carries a risk of transforming into a more aggressive blood cancer called Acute Myeloid Leukemia (AML).
Defining Chronic Myelomonocytic Leukemia
CMML is classified as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap disorder, exhibiting characteristics of two different blood disorders. The myelodysplastic component involves the ineffective production of mature, healthy blood cells, often leading to low counts of red blood cells or platelets. The myeloproliferative feature involves the overproduction of myeloid cells, particularly monocytes. This dual nature means cells are both overproduced and dysfunctional in the bone marrow.
The defining cellular feature is sustained monocytosis, meaning the absolute count of monocytes in the peripheral blood is elevated. These abnormal monocytes accumulate in the bone marrow, crowding out space needed for healthy blood cell production. This abnormal maturation process, known as dysplasia, means the mature cells that are produced often do not function correctly. Depending on the white blood cell count, CMML is subclassified into myelodysplastic (MD-CMML) or myeloproliferative (MP-CMML) variants.
Who is Affected and What Causes It
CMML predominantly affects older individuals, with the median age at diagnosis typically around 70 to 72 years. It is rare in individuals under 50, and incidence rises sharply after age 60. There is also a slight male predominance.
The exact cause of CMML is not fully understood, but it results from acquired genetic mutations in the blood-forming stem cells, rather than being inherited. These somatic mutations lead to an uncontrolled and abnormal growth pattern. Over 90% of CMML patients have at least one detectable mutation in genes regulating cell growth and differentiation.
The most frequently altered genes include TET2 (up to 60% of cases), SRSF2 (up to 50%), and ASXL1 (about 40%). These genes are involved in processes like DNA methylation and RNA splicing, and their mutations disrupt the normal maturation of blood cells. Environmental factors, such as previous exposure to chemotherapy, radiation, or certain industrial chemicals, are considered risk factors contributing to these genetic changes.
Recognizing the Signs and Symptoms
The early stages of CMML are often subtle or asymptomatic, sometimes first detected during routine blood work. When symptoms appear, they result from low counts of healthy blood cells (cytopenias) or the accumulation of abnormal monocytes in organs. Persistent fatigue and weakness are common complaints, typically signaling anemia caused by a lack of healthy red blood cells.
Patients may experience frequent infections due to dysfunctional white blood cells or easy bruising and bleeding from a low platelet count. Symptoms related to the overgrowth of abnormal cells include an enlarged spleen (splenomegaly), which can cause discomfort or fullness in the upper left abdomen. Other systemic complaints include unexplained weight loss, night sweats, and low-grade fevers.
How CMML is Diagnosed
Diagnosis begins with a complete blood count (CBC) to measure blood cell levels. A consistent finding is persistent absolute monocytosis, defined as a monocyte count of at least \(1 \times 10^9\) cells per liter of blood, sustained for at least three months. A peripheral blood smear is also examined under a microscope to look for abnormal or immature cells and confirm the excessive monocytes.
Confirmation requires a bone marrow biopsy and aspiration, collecting samples of the liquid and tissue for examination. The pathologist assesses cellularity, looks for signs of dysplasia in the myeloid cell lines, and determines the percentage of immature blast cells. Blast cells in the blood or bone marrow must be less than 20% to distinguish CMML from acute myeloid leukemia.
Specialized molecular and cytogenetic testing is performed on blood or bone marrow samples to look for specific chromosomal abnormalities or gene mutations. Identifying mutations in genes like TET2 or SRSF2 helps confirm the diagnosis and classify the disease. This analysis is also used to exclude similar disorders, such as Chronic Myeloid Leukemia (CML), which is defined by the absence of the Philadelphia chromosome.
Current Treatment Approaches
Treatment for CMML is tailored to the patient’s specific disease features, risk classification, and overall health status, as it primarily affects older adults. For asymptomatic or lower-risk patients, watchful waiting or active surveillance is adopted. Supportive care is a component of most treatment plans, including red blood cell or platelet transfusions to manage cytopenias and antibiotics to treat infections.
The drug hydroxyurea is used to control the overproduction of white blood cells and manage symptoms like an enlarged spleen in patients with the myeloproliferative variant. For higher-risk disease or significant dysplasia, hypomethylating agents (HMAs), such as azacitidine and decitabine, are the standard disease-modifying therapies. These medications alter gene expression in cancer cells, leading to improved blood counts and delaying progression to AML.
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only treatment with the potential to offer a cure for CMML. This procedure replaces the patient’s diseased bone marrow with healthy donor stem cells. However, due to the high median age and presence of other medical conditions in most CMML patients, allo-SCT is only a viable option for a small fraction of individuals.