Chronic Myelomonocytic Leukemia (CMML) is a type of blood cancer originating in the bone marrow, the soft tissue where blood cells are made. This malignancy is characterized by the overproduction of monocytes, a specific type of white blood cell, while the production of other blood cells can be impaired. CMML is officially classified as a rare disease, and understanding its definition and statistical frequency provides context for this complex condition.
Defining Chronic Myelomonocytic Leukemia
Chronic Myelomonocytic Leukemia is a clonal disorder of the hematopoietic stem cells, meaning it starts from a single mutated cell in the bone marrow. It is considered a hybrid cancer because it displays features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Therefore, the World Health Organization (WHO) classifies CMML as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndrome.
The term “chronic” indicates that the disease typically progresses slowly, while “myelomonocytic” refers to the specific blood cells affected. The disease is defined by a persistent and excessive number of monocytes in the peripheral blood, typically at least \(0.5 \times 10^9\)/L, and making up at least 10% of the white blood cell count. These monocytes are often abnormal and immature, and their overgrowth can crowd out the production of healthy red blood cells, platelets, and other white blood cells. CMML also involves dysplasia, the abnormal appearance of cells, in at least one other lineage of myeloid blood cells.
The Statistical Rarity of CMML
Chronic Myelomonocytic Leukemia is statistically considered a rare disease. The overall age-adjusted incidence rate in the United States is approximately \(0.35\) to \(0.4\) cases per 100,000 people per year. This low frequency results in an estimated 2,000 new cases diagnosed each year in the U.S.
For context, a more common blood cancer like Chronic Myeloid Leukemia (CML) has an incidence rate of about \(2.0\) cases per 100,000 men and women per year, making CMML significantly less frequent. Because of its low incidence, CMML qualifies as a rare disease under definitions used by major health jurisdictions, such as the U.S. Orphan Drug Act. Surveillance, Epidemiology, and End Results (SEER) program data confirms the age-adjusted incidence rate has remained stable over time.
Demographic Distribution and Risk Factors
Despite its overall rarity, the incidence of CMML is concentrated within specific demographic groups, particularly older adults. The median age at diagnosis is around 72 years, and nearly 90% of cases occur in patients over the age of 60. Its frequency increases markedly in the elderly, reaching an incidence of \(2.5\) cases per 100,000 individuals over 70 years.
CMML also exhibits a distinct sex distribution, affecting men more frequently than women. The age-adjusted incidence rate is more than double in males (\(0.6/100,000\)) compared to females (\(0.3/100,000\)), with male patients accounting for roughly 73% of cases. While most cases arise sporadically without an identifiable cause, certain risk factors are recognized. These include prior exposure to chemotherapy or radiation therapy, which can lead to therapy-related CMML. However, the majority of patients do not have a known antecedent exposure.
CMML Subtypes and Diagnostic Complexity
The rarity of CMML, combined with its dual nature as an MDS/MPN overlap syndrome, contributes to diagnostic complexity. The WHO classification system divides CMML into two main categories based on the percentage of blast cells, which are immature precursor cells, found in the blood and bone marrow.
CMML-1 is defined by having less than 5% blasts in the peripheral blood and less than 10% in the bone marrow. CMML-2 includes cases with 5% to 19% blasts in the blood or 10% to 19% in the bone marrow, and the presence of Auer rods also places a case into this subtype.
Beyond the blast count, CMML is further categorized based on the total white blood cell (WBC) count:
Myelodysplastic Type (MD-CMML)
This type has a WBC count below \(13 \times 10^9\)/L.
Myeloproliferative Type (MP-CMML)
This type has a WBC count of \(13 \times 10^9\)/L or greater.
Diagnosis relies on a combination of persistent monocytosis, bone marrow biopsy to assess cellular morphology and blast percentage, and genetic testing. Nearly 90% of CMML patients harbor one or more somatic mutations, such as in the TET2, SRSF2, or ASXL1 genes.