Chronic myelomonocytic leukemia (CMML) is a blood cancer of older adults. Its defining feature is a persistently high number of monocytes, a type of white blood cell, in the blood. It is caused by acquired mutations in blood-forming stem cells and is diagnosed with blood counts, a bone marrow biopsy, and genetic testing. Treatment ranges from watchful waiting to hypomethylating drugs, and a stem cell transplant is the only potential cure. What makes CMML complex is that it combines features of two disease families.
What Is CMML Leukemia?
CMML sits on the border between myelodysplastic syndromes (MDS), where the marrow produces abnormal, ineffective cells, and myeloproliferative neoplasms (MPN), where it overproduces cells. Patients can show both patterns at once: low counts in some cell lines and high counts in others. Our comprehensive overview of CMML leukemia covers the classification in more detail for clinicians.
The name leads to frequent confusion with other conditions. CMML is not chronic myelogenous leukemia (CML), which is driven by the BCR::ABL1 fusion gene and treated with targeted tyrosine kinase inhibitors. It is also different from acute myelomonocytic leukemia, an acute leukemia with many immature blast cells. The broader family is described in our guide to myelomonocytic leukemia.
CMML is uncommon, and many patients and families have never heard of it before diagnosis. If you are new to blood cancers, our guide to hematological disorders for patients and caregivers explains the basic terms used in this article, such as blasts, marrow, and blood counts.
CMML at a glance
| Feature | CMML | CML | Acute myelomonocytic leukemia |
|---|---|---|---|
| Key blood finding | Persistent monocytosis | High neutrophils and precursors | Many blasts |
| BCR::ABL1 fusion | Absent | Present | Absent |
| Blasts in blood or marrow | Under 20% | Low in chronic phase | 20% or more |
| Pace | Chronic, variable | Chronic phase controllable for years | Rapid; needs urgent treatment |
What Causes CMML?
CMML starts when a stem cell in the bone marrow acquires mutations that give its descendants a growth advantage. These mutations are acquired during life, not inherited. The genes most often involved include:
- TET2, an epigenetic regulator and the most frequently mutated gene in CMML
- SRSF2, part of the RNA-splicing machinery
- ASXL1, another epigenetic regulator. Truncating mutations are associated with a worse outlook.
- RAS-pathway genes (NRAS, KRAS, CBL), linked to the proliferative form
- RUNX1, a transcription factor important for normal blood formation
Risk factors
Age is the main risk factor. CMML is typically diagnosed around age 70 or later and is more common in men. Previous chemotherapy or radiotherapy raises risk, and in that setting the disease is called therapy-related. Long-term exposure to benzene has been linked to myeloid cancers in general. Most patients have no identifiable trigger.
Signs and Symptoms
Many cases are found incidentally on a routine blood count. When symptoms occur, they reflect either low blood counts or overproduction of cells:
- Anemia: fatigue, breathlessness, pallor
- Low platelets: easy bruising and bleeding
- Proliferative features: an enlarged spleen causing early fullness or left-sided discomfort, weight loss, night sweats, fever
- Infections caused by poorly functioning white cells
Symptoms like these are shared by many hematologic disorders, so laboratory confirmation is essential.
How CMML Is Diagnosed
Current World Health Organization criteria require persistent monocytosis, defined as an absolute monocyte count of at least 0.5 × 10⁹/L that also makes up at least 10% of white cells. Blasts must be below 20% (otherwise the disease is acute leukemia), and other causes must be excluded.
The diagnostic workup
- Complete blood count and blood smear: confirms monocytosis and looks for abnormal-looking cells.
- Bone marrow aspirate and biopsy: assesses blast percentage, dysplasia, and cellularity.
- Cytogenetics: looks for chromosome changes and excludes BCR::ABL1 (CML) and other defining rearrangements.
- Next-generation sequencing: identifies mutations such as TET2, SRSF2, and ASXL1, which supports the diagnosis and helps predict outlook.
Reactive causes of monocytosis, such as chronic infection, inflammatory disease, and recovery after chemotherapy, have to be ruled out first.
Subtypes
CMML is divided by white cell count into myelodysplastic CMML (white cells below 13 × 10⁹/L) and myeloproliferative CMML (13 × 10⁹/L or above). It is also graded by blast percentage into CMML-1 and CMML-2, with CMML-2 carrying a higher risk of progression to acute leukemia.
Treatment Options
Treatment depends on risk, symptoms, age, and fitness. Specialists use prognostic scores that combine blood counts, blasts, chromosome findings, and mutations to guide decisions.
- Observation: lower-risk patients with stable counts and no symptoms may simply be monitored.
- Supportive care: red cell transfusions, growth factors for anemia in selected patients, and prompt treatment of infections.
- Hydroxyurea: an oral drug used to control high white counts and spleen size in proliferative disease.
- Hypomethylating agents: azacitidine and decitabine modify abnormal gene silencing. They can improve blood counts and reduce transfusion needs in higher-risk disease.
- Allogeneic stem cell transplant: the only treatment with curative potential. It is reserved for fit patients with higher-risk disease because of its toxicity.
Living with CMML
For many people, CMML is managed as a long-term condition rather than a one-off treatment. Regular blood counts track how the disease is behaving, and treatment can be stepped up if counts fall, the spleen enlarges, or blasts rise. In my practice, I encourage patients to keep a simple record of transfusions, infections, and symptoms. It makes clinic reviews more productive and helps spot changes early.
Clinical trials are testing targeted drugs and combinations. Joining a trial is a reasonable option to discuss with your specialist.
When to See a Doctor
See a doctor if you have ongoing fatigue, unexplained bruising, frequent infections, fevers or night sweats, or fullness under the left ribs. If a blood test has shown a persistently raised monocyte count, ask for a referral to a hematologist. Anyone already diagnosed with CMML should report new fevers, bleeding, or rapid changes in symptoms promptly.
Frequently Asked Questions
Is CMML a type of leukemia or MDS?
It is both. The classification places it in a combined MDS/MPN category, because it shows features of both. It is still treated as a form of chronic leukemia.
Can CMML turn into acute leukemia?
Yes, a proportion of patients progress to acute myeloid leukemia. The risk is higher with more blasts and certain mutations, which is why regular monitoring matters.
Is CMML inherited?
No. The mutations that cause it are acquired in the bone marrow during life, so it is not passed to children.
Can CMML be cured?
Only an allogeneic stem cell transplant offers a chance of cure. Other treatments aim to control the disease, improve blood counts, and preserve quality of life.
Key Takeaways
- CMML is defined by persistent monocytosis and combines features of MDS and MPN.
- It is caused by acquired mutations, most often in TET2, SRSF2, and ASXL1.
- Diagnosis requires blood tests, a bone marrow biopsy, cytogenetics, and molecular testing, plus exclusion of CML and reactive causes.
- Treatment ranges from monitoring to hypomethylating agents, and a transplant is the only curative option.
