Chronic Myelomonocytic Leukemia (CMML) is a rare type of blood cancer that originates in the bone marrow, the soft tissue inside bones where blood cells are made. This condition involves the overproduction and improper development of certain white blood cells called monocytes. CMML can affect individuals of any age, though it is most commonly diagnosed in older adults, typically around 71 to 74 years old.
Understanding Chronic Myelomonocytic Leukemia (CMML)
CMML is classified as a hybrid myelodysplastic/myeloproliferative neoplasm (MDS/MPN). This means it exhibits characteristics of both myelodysplastic syndromes (MDS), where blood cells do not mature properly, and myeloproliferative neoplasms (MPN), where there is an overproduction of blood cells. The disease is chronic, developing slowly over time, but carries a risk of transforming into acute myeloid leukemia (AML) in about 15% to 30% of cases.
Is CMML Inherited or Acquired?
CMML is primarily an acquired condition, developing during a person’s lifetime due to random genetic changes, known as somatic mutations, that arise in blood-forming cells within the bone marrow. These mutations are not present at birth and cannot be inherited by offspring. The incidence of CMML significantly increases with age, particularly in individuals over 70, suggesting these acquired mutations accumulate over time.
While most CMML cases are acquired, a very small percentage of individuals may have a hereditary predisposition. This predisposition is linked to inherited genetic alterations, called germline mutations, found in genes like GATA2 or SRP72. Unlike somatic mutations, germline mutations are present in all cells from birth and can be passed from parents to children. Therefore, a family history of CMML or related blood disorders might indicate an underlying inherited susceptibility.
Genetic Changes Driving CMML
Among the most frequently mutated genes in CMML patients are TET2, SRSF2, and ASXL1, each found in approximately 35% to over 60% of cases. Mutations in TET2 are often considered early events in CMML development, affecting DNA demethylation and epigenetic regulation.
Other commonly observed mutations include those in the RAS pathway genes such as NRAS and KRAS, found in around 14% and 8% of patients respectively. These mutations can impact cellular signaling pathways, contributing to the uncontrolled growth of monocytes. Mutations in genes like RUNX1, EZH2, and CBL are also found in a smaller percentage of patients and can influence disease progression and prognosis.
Recognizing and Diagnosing CMML
Recognizing CMML can be challenging because its initial symptoms are often non-specific and can overlap with other conditions. Common symptoms include persistent fatigue, unexplained weight loss, low-grade fevers, easy bruising or bleeding, and recurrent infections. An enlarged spleen, known as splenomegaly, is also a frequent finding, occurring in approximately half of CMML cases. Some individuals may not experience noticeable symptoms and are diagnosed incidentally during routine blood tests.
Diagnosis for CMML begins with a complete blood count (CBC), which reveals a sustained increase in monocytes in the peripheral blood, usually greater than 1 billion cells per liter and accounting for more than 10% of white blood cells. If CMML is suspected, a bone marrow aspiration and biopsy are performed to examine blood-forming cells directly. This assesses cellularity, abnormal cell development (dysplasia), and the percentage of immature blood cells called blasts, which must be less than 20% for a CMML diagnosis. Specialized genetic tests, such as fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS), are also utilized to identify specific chromosomal abnormalities and gene mutations that confirm the diagnosis and provide prognostic information.
Treatment Approaches for CMML
Treatment for CMML is tailored to the individual patient, considering factors such as disease subtype, symptoms, overall health, and specific genetic mutations. Supportive care is a common approach, focusing on managing symptoms and improving quality of life, which may include blood transfusions for anemia. For patients with higher white blood cell counts, medications like hydroxyurea can be used to reduce cell proliferation.
Hypomethylating agents, such as azacitidine or decitabine, are a class of chemotherapy drugs approved for CMML treatment. These agents work by modifying gene expression in cancer cells and can help improve blood counts and reduce the risk of transformation to AML. In select cases, particularly for younger and fitter patients, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative option. This intensive procedure involves replacing the patient’s diseased bone marrow with healthy stem cells from a donor.