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 produced. It is characterized by an overproduction of monocytes, a specific type of white blood cell, and also exhibits features seen in myelodysplastic syndromes. These features include the ineffective production of other blood cell types, leading to potential shortages of red blood cells and platelets.
Understanding Chronic Myelomonocytic Leukemia
CMML is classified as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Myelodysplastic syndromes involve the bone marrow producing abnormal, dysfunctional blood cells that often die prematurely. Myeloproliferative neoplasms, conversely, are marked by an overproduction of mature blood cells. CMML uniquely combines these aspects, showing both ineffective blood cell production and an excess of monocytes.
This complex disorder originates from mutations within hematopoietic stem cells, which are the foundational cells in the bone marrow responsible for creating all blood cell types. CMML is frequently linked to specific genetic mutations. Common mutations involve genes such as TET2, SRSF2, and ASXL1. Mutations in the RAS pathway genes are also observed. CMML typically affects older adults, with most diagnoses occurring in individuals over 60 years of age, and it is more prevalent in men.
Signs and Symptoms
The signs and symptoms of CMML can be non-specific and may be discovered incidentally during routine blood tests. Common manifestations include persistent fatigue and weakness, often stemming from anemia. Shortness of breath and pale skin can also result from anemia.
Individuals may experience easy bruising or bleeding due to low platelet counts. A reduced number of functional white blood cells can lead to recurrent or prolonged infections. Other systemic symptoms include unexplained weight loss, fever, night sweats, and a diminished appetite. Physical examination might reveal an enlarged spleen (splenomegaly) or liver (hepatomegaly), as monocytes can accumulate in these organs. An enlarged spleen can cause discomfort or a feeling of fullness in the upper left abdomen.
Diagnosis of CMML
Diagnosing CMML involves a combination of laboratory tests and examinations of bone marrow. A complete blood count (CBC) is typically the initial step, revealing a persistently elevated monocyte count in the peripheral blood (usually >1 x 10^9/L and >10% of white blood cells). This monocytosis must be sustained for at least three months for diagnosis.
A bone marrow aspiration and biopsy are also performed to examine the cellular composition and detect abnormal cells and dysplasia. For a CMML diagnosis, immature blood cells, known as blasts, must constitute less than 20% of the cells in both the peripheral blood and bone marrow. Cytogenetic and molecular genetic testing are instrumental in identifying specific chromosomal abnormalities or gene mutations, such as those in TET2, SRSF2, and ASXL1, offering prognostic insights. Other conditions with similar blood count abnormalities, such as chronic myeloid leukemia (CML), must be excluded. CML is differentiated by the Philadelphia chromosome.
Treatment Approaches
Treatment strategies for CMML are individualized, based on disease subtype, severity, and overall health. For patients who are asymptomatic or have low-risk disease, a “watchful waiting” approach may be adopted, involving regular monitoring. When intervention is needed, hypomethylating agents (HMAs) such as azacitidine or decitabine are often used to improve blood counts and potentially slow disease progression. These agents can also improve progression-free survival when used before an allogeneic stem cell transplant.
For more aggressive forms of CMML or those with higher blast counts, chemotherapy may be considered. Allogeneic stem cell transplantation (allo-SCT) is currently the only potentially curative treatment option for eligible patients. This procedure involves replacing the diseased bone marrow with healthy stem cells from a donor, though it carries significant risks. Supportive care measures are also important to manage symptoms and complications, including blood transfusions for anemia, growth factors to stimulate blood cell production, and antibiotics to combat infections.
Prognosis and Outlook
The prognosis for individuals with CMML is highly variable, influenced by several factors including CMML subtype, genetic mutations, patient age, and general health. CMML can present with features resembling either myelodysplastic syndromes (MD-CMML) or myeloproliferative neoplasms (MP-CMML), with differing outcomes. For instance, patients with isolated TET2 mutations may have a longer median overall survival, while those with isolated ASXL1 mutations tend to have shorter survival.
A significant concern in CMML is its potential to transform into acute myeloid leukemia (AML), which occurs in approximately 15-30% of cases over three to five years. The presence of certain AML-associated mutations, such as CEBPA, FLT3, or NPM1, can worsen the prognosis in CMML. Ongoing research aims to enhance the understanding of CMML and develop more effective treatment options, improving patient outcomes and quality of life.