A diagnosis of leukemia, or blood cancer, is a frightening and life-changing event. While many people are familiar with more common types of leukemia, some forms are rare and complex, making them difficult to understand. One such condition is Chronic Myelomonocytic Leukemia (CMML), a unique and challenging type of blood cancer that primarily affects older adults. CMML is considered a rare “overlap” syndrome, meaning it has features of two different kinds of bone marrow disorders. While there is no simple cure for most patients, understanding this complex disease, its diagnosis, and the available treatment strategies is the first and most important step for patients and their families to navigate the journey ahead and manage the condition to maintain the best possible quality of life.

Chronic Myelomonocytic Leukemia is a clonal hematopoietic disorder. This means it is a cancer that starts from a single faulty blood-forming stem cell in the bone marrow. The defining feature of CMML is its unique position as an “overlap” syndrome, sharing characteristics of two distinct groups of bone marrow diseases:

1. Myelodysplastic Syndromes (MDS): These are conditions where the bone marrow is unable to produce enough healthy, mature blood cells. The cells that are produced are abnormal in shape and function (a feature called “dysplasia”), leading to low blood counts (cytopenias).
2. Myeloproliferative Neoplasms (MPN): These are conditions where the bone marrow goes into overdrive and produces far too many of one or more types of blood cells (“proliferation”).

CMML has features of both. The bone marrow is often hypercellular (overcrowded and working hard) yet produces dysfunctional red blood cells and platelets, leading to anemia and bleeding risks, much like in MDS. At the same time, it has a key proliferative feature: it produces a persistently high number of a specific type of white blood cell called a monocyte. This defining characteristic, a high blood monocyte count is the hallmark of the disease.

A helpful analogy is to think of the bone marrow as a large factory that produces three types of vehicles: red cars (red blood cells), various white security vans (white blood cells), and small repair scooters (platelets).

• In MDS, the factory machinery is faulty, and it churns out poorly made, defective vehicles that quickly break down, leading to shortages on the city streets.
• In MPN, one specific assembly line gets stuck in overdrive, flooding the city with one type of vehicle.
• CMML is like a factory with both problems at once. The overall machinery is faulty, leading to shortages of red cars and repair scooters. Simultaneously, the specific assembly line for one type of security van, the monocyte, is stuck in overdrive, producing a massive, uncontrolled number of them. This combination of ineffective production (dysplasia) and overproduction (proliferation) is what defines this unique overlap syndrome.

Clinically, I’ve seen that CMML often hides in plain sight, patients may present with vague symptoms like fatigue or frequent infections, and the diagnosis only becomes clear after a routine blood test reveals elevated monocytes.

CMML is caused by the acquisition of somatic gene mutations in a hematopoietic stem cell. “Somatic” means these mutations are not inherited from a parent but occur by chance during a person’s lifetime. These mutations give the faulty stem cell a survival advantage, allowing it to clone itself and take over the bone marrow.

This “master” leukemic stem cell then produces blood cells that are both dysfunctional and, in the case of monocytes, overabundant. Researchers have identified several genes that are commonly mutated in CMML. Many of these genes, such as TET2, SRSF2, and ASXL1, are involved in epigenetic regulation or RNA splicing, complex processes that control how other genes are read and used. A mutation here disrupts the entire orderly program of blood cell development, leading to the chaos seen in CMML. Why these initial mutations occur is mostly unknown.

I’ve often seen cases where a patient is referred to hematology after a routine check-up reveals elevated white cell counts and CMML wasn’t even suspected initially.

CMML is neither inherited nor contagious. It develops when DNA mutations accumulate in bone marrow stem cells, typically with age. For the vast majority of patients, CMML arises de novo, meaning it develops with no known preceding cause or exposure. However, several factors are known to increase the risk of developing this and other myeloid cancers.

The primary risk factors include:

• Age: This is the biggest risk factor. CMML is a disease of older adults, with the average age at diagnosis being between 70 and 75 years. It is very rare in people under 50.
• Gender: The disease is more common in men than in women, for reasons that are not clear.
• Prior Cancer Treatment: Previous exposure to certain chemotherapy drugs or radiation therapy for another cancer can damage the DNA of bone marrow stem cells, increasing the risk of developing a “therapy-related” myeloid neoplasm like CMML years later.
• Environmental Exposures: Long-term occupational exposure to certain chemicals, such as benzene and some industrial solvents or pesticides, has been linked to an increased risk of bone marrow disorders.

In my experience, most patients with CMML have no clear trigger, it’s often age-related and discovered incidentally, but explaining the underlying mutations helps them understand that this is a biological shift, not something they caused.

Symptoms of CMML vary widely depending on how advanced the disease is and which blood cell lines are affected. Many people are diagnosed incidentally on a routine blood test that shows an unexplained high white blood cell count. When symptoms do occur, they are a direct result of bone marrow dysfunction.

The symptoms can be grouped into two main categories:

1. Symptoms from Cytopenias (Low Blood Counts)

These symptoms are caused by the bone marrow’s failure to produce enough healthy, functional blood cells.

• Anemia (low red cells): This is the most common finding and leads to persistent fatigue, weakness, pale skin, and shortness of breath with exertion.
• Thrombocytopenia (low platelets): This can cause easy bruising, prolonged bleeding from cuts, frequent nosebleeds, or the appearance of tiny, red pinpoint dots on the skin (petechiae).
• Neutropenia (low functional white blood cells): Even though the total white blood cell count may be high due to the monocytes, the number of infection-fighting neutrophils can be low, leading to recurrent or frequent infections.

2. Symptoms from Monocytosis and Organ Infiltration

These symptoms are caused by the massive overproduction and accumulation of the abnormal monocytes.

• Splenomegaly (Enlarged Spleen): This is a very common feature. The excess monocytes can build up in the spleen, causing it to become enlarged. This can lead to a feeling of fullness or pain in the upper left side of the abdomen.
• Constitutional “B Symptoms”: This classic triad of cancer-related symptoms includes unexplained fever, drenching night sweats, and unintentional weight loss.
• Skin Rashes or Lesions: The leukemic monocytes can sometimes infiltrate the skin, causing rashes or raised lumps.

Patients often tell me they thought they were just “aging faster than usual” but when fatigue, infections, and weight loss all combine, that’s when CMML often comes into view.

Diagnosing CMML requires a combination of blood tests, bone marrow evaluation, and genetic analysis. It’s important to rule out other causes of elevated monocytes or related blood cancers.

1. Complete Blood Count (CBC) with Differential: This is the initial blood test that provides the first major clue. The hallmark and absolute requirement for a CMML diagnosis is a persistent absolute monocytosis, meaning the monocyte count is consistently elevated (typically >1.0 x 10⁹/L) and makes up more than 10% of the white blood cells. The CBC will also often show anemia and/or a low platelet count.
2. Peripheral Blood Smear: A pathologist examines a blood sample under a microscope. They will confirm the high number of monocytes and will look for dysplastic (abnormally shaped) cells and for the presence of any immature “blast” cells.
3. Bone Marrow Aspiration and Biopsy: This is an essential and definitive test. A hematologist will take a sample of liquid marrow (aspirate) and a small core of solid marrow (biopsy) from the back of the hip bone. The pathologist will examine these samples to:
   • Make sure bone marrow is hypercellular (overcrowded).
   • Look for dysplasia (abnormal development) in at least one of the three main cell lines.
   • Determine the percentage of blast cells. The percentage of blasts is a critical factor in determining disease risk and prognosis.
4. Cytogenetics and Molecular Testing: The bone marrow sample is also sent for advanced testing.
   • Cytogenetics looks for large-scale abnormalities in the chromosomes.
   • Molecular Testing (Next-Generation Sequencing) is now standard. This looks for specific gene mutations (like TET2, ASXL1, etc.) that are characteristic of CMML. These mutations are crucial for confirming the diagnosis and, most importantly, for risk stratification, which helps doctors predict the course of the disease and decide on the best treatment approach.

Clinically, I’ve seen that the genetic testing results are especially helpful in prognosis, certain mutations, like ASXL1, are associated with a more aggressive course and guide how closely we monitor the patient.

Treatment for CMML depends on disease severity, symptom burden, patient age, overall health, and whether the disease is progressing.

1. Low-Risk or “Myelodysplastic-like” CMML

The focus is supportive care.

• Blood and Platelet Transfusions as needed to manage severe anemia or bleeding.
• Growth Factors, such as erythropoiesis-stimulating agents (ESAs), to help the bone marrow produce more red blood cells.
• Antibiotics to treat infections quickly.

2. High-Risk or “Myeloproliferative-like” CMML

The goal is to control the disease and try to improve survival.

• Hypomethylating Agents (HMAs): Drugs like azacitidine or decitabine are often the first-line therapy. These are a form of low-intensity chemotherapy that can improve blood counts and slow disease progression.
• Hydroxyurea: This is an oral chemotherapy drug that is primarily used to lower a very high white blood cell and monocyte count. It can be very effective at reducing the size of an enlarged spleen and controlling constitutional symptoms.
• Allogeneic Stem Cell Transplant (HSCT): This is the only potentially curative treatment for CMML. However, it is an intensive and high-risk procedure that is only an option for a small minority of patients who are younger, medically fit, and have a suitable matched donor.

In my experience, the choice of when to start treatment is often more emotional than medical, many patients struggle with the idea of “watching and waiting,” even though it’s the best course early on. Communication and trust are key.

Chronic Myelomonocytic Leukemia is a rare and complex blood cancer that uniquely combines features of both myelodysplastic and myeloproliferative disorders, defined by a high monocyte count. Primarily a disease of older adults, its treatment is risk-stratified. While a cure for CMML is only possible for a select few via a stem cell transplant, a proactive management plan can make a significant difference. Clinically, I always remind patients that CMML doesn’t mean immediate chemotherapy. In many cases, we can build a long-term care plan tailored to their lifestyle and goals.

1. Leukemia & Lymphoma Society (LLS). (n.d.). Chronic Myelomonocytic Leukemia. Retrieved from https://www.lls.org/leukemia/chronic-myelomonocytic-leukemia
2. National Cancer Institute (NCI). (2023). Chronic Myelomonocytic Leukemia Treatment (PDQ®)–Patient Version. Retrieved from https://www.cancer.gov/types/leukemia/patient/cmm-treatment-pdq
3. The MDS Foundation. (n.d.). CMML. Retrieved from https://www.mds-foundation.org/what-is-mds/cmm/