Chronic Myelomonocytic Leukemia: Symptoms, Types, Causes and Treatment

Chronic Myelomonocytic Leukemia (CMML) is a rare and complex blood disorder that sits at the crossroads of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). It primarily affects older adults, presenting with a bewildering mix of symptoms and clinical features, and can progress to acute leukemia in some patients. In this article, we break down the essential facts about CMML—what it looks like, its main forms, why it happens, and how it’s currently treated—using the latest research and expert recommendations.

Symptoms of Chronic Myelomonocytic Leukemia

CMML is notorious for its variable and often subtle symptoms, which can make diagnosis challenging. Early detection is crucial, as symptoms can overlap with other blood disorders and may significantly impact quality of life.

Symptom	Description	Impact	Source
Fatigue	Persistent tiredness due to anemia	Limits daily activities	1 2 6
Infections	Increased susceptibility from low white blood cells	Frequent/severe infections	1 2
Bleeding/bruising	Easy bruising or bleeding from low platelets	Risk of hemorrhage	1 2
Splenomegaly	Enlarged spleen, sometimes with abdominal discomfort	Fullness/pain, early satiety	2 12
Fever, weight loss	Constitutional symptoms, especially in advanced cases	Indicate disease progression	2 12

Table 1: Key Symptoms

Understanding the Symptoms

CMML’s symptoms mostly stem from ineffective blood cell production and the abnormal increase of monocytes—a type of white blood cell.

Fatigue and Anemia

• Most patients experience persistent fatigue, which is often the first sign. This is due to anemia (low red blood cell counts) caused by the bone marrow’s inability to produce enough healthy cells 1 2.
• Anemia may also lead to shortness of breath, pale skin, and general weakness.

Increased Risk of Infections

• A shortage of healthy white blood cells impairs the immune system, making patients vulnerable to frequent or severe infections 1 2.
• Even minor infections can become significant medical issues.

Bleeding and Bruising

• Low platelet counts (thrombocytopenia) lead to easy bruising, nosebleeds, gum bleeding, or excessive bleeding from small cuts 1 2.
• Some patients may notice pinpoint red spots on the skin (petechiae).

Enlarged Spleen (Splenomegaly)

• An enlarged spleen is common, particularly in the proliferative type of CMML 2 12.
• This may cause abdominal discomfort, fullness, or pain, and sometimes early satiety (feeling full quickly when eating).

Constitutional Symptoms

• In advanced or higher-risk disease, patients may develop fevers, night sweats, and unintended weight loss 2 12.
• These symptoms often signal disease progression or transformation to acute leukemia.

Types of Chronic Myelomonocytic Leukemia

CMML is not a one-size-fits-all disease. Its subtypes reflect differences in blood counts, genetics, and clinical features, all of which have important implications for treatment and prognosis.

Type/Subtype	Defining Feature(s)	Clinical Implications	Source
Myelodysplastic CMML	WBC < 13 x 10⁹/L	Resembles MDS; more cytopenias	12 7
Myeloproliferative CMML	WBC ≥ 13 x 10⁹/L	Splenomegaly, higher risk symptoms	12 2
Overt/Classic CMML	Persistent monocytosis (≥1 x 10⁹/L)	Main diagnostic criterion	5 7
Oligomonocytic CMML	Monocytes ≥10% but <1 x 10⁹/L	Early/indolent phase; may progress	5 7

Table 2: CMML Types & Variants

Subtypes and Their Features

Myelodysplastic vs. Myeloproliferative CMML

• Myelodysplastic CMML: Characterized by lower white blood cell (WBC) counts (<13 x 10⁹/L), more pronounced cytopenias (anemia, neutropenia, thrombocytopenia), and features similar to myelodysplastic syndromes 12 7.
  • Patients often experience fatigue, infections, and bleeding as major issues.
• Myeloproliferative CMML: Defined by higher WBC counts (≥13 x 10⁹/L), prominent splenomegaly, and sometimes constitutional symptoms like fever and weight loss 12 2.
  • These patients may present with symptoms related to high cell counts and spleen enlargement.

Overt (Classic) CMML

• The classic or "overt" form is diagnosed when persistent monocytosis (≥1 x 10⁹/L) is present, along with dysplasia in at least one blood cell lineage 5 7.
• This is the most straightforward presentation and follows established diagnostic criteria.

Oligomonocytic CMML

• Some patients have increased monocyte percentages (≥10%) but do not meet the absolute monocytosis threshold 5 7.
• This "oligomonocytic" variant may represent an early or pre-CMML phase and can progress to classical CMML over time.
  • These patients are typically younger and have lower overall mutation burdens.

Causes of Chronic Myelomonocytic Leukemia

While the exact cause of CMML is not fully understood, it is now clear that CMML arises from a complex interplay of genetic, age-related, and possibly environmental factors.

Cause/Factor	Role in Disease	Additional Notes	Source
Age-related mutations	Accumulation over time in stem cells	Disease of the elderly	8 10
Gene mutations (e.g., TET2, SRSF2, ASXL1)	Drive clonal expansion and disease features	Most patients have multiple mutations	3 9 8
Clonal hematopoiesis	Abnormal blood cell production	Precedes overt CMML	8 10
Cytogenetic changes	Additional risk stratification	~30% have chromosomal changes	9

Table 3: CMML Causative Factors

Genetics and Disease Development

Age-Related Mutations

• CMML is almost exclusively a disease of older adults, often developing after decades of silent mutation accumulation in hematopoietic stem cells 8 10.
• This process, known as clonal hematopoiesis, increases as people age and sets the stage for further genetic “hits” that drive malignancy.

Key Genetic Mutations

• The most commonly mutated genes in CMML are TET2 (~60%), SRSF2 (~50%), and ASXL1 (~40%) 3 9 8.
  • These genes play critical roles in DNA methylation, RNA splicing, and chromatin modification.
• Other frequent mutations include RUNX1, SETBP1, KRAS, NRAS, CBL, EZH2 8 9.
  • Many patients have mutations in two or more of these genes, and a higher mutation burden is linked with worse outcomes 8.

Clonal Evolution and Progression

• CMML typically begins with a “founder” or ancestral mutation (often in TET2), which gives a survival advantage to a stem cell 10 3.
• Secondary mutations (e.g., SRSF2, RAS pathway genes) drive progression to overt CMML and, in some cases, to acute leukemia 10 3.
• The specific combination and hierarchy of mutations influence the clinical subtype (dysplastic vs. proliferative) and prognosis 3.

Cytogenetic Abnormalities

• About 30% of CMML patients have chromosomal abnormalities such as trisomy 8, monosomy 7, or deletions in 7q and 20q 9.
• These changes are used in modern prognostic scoring systems.

Treatment of Chronic Myelomonocytic Leukemia

Treating CMML is challenging because of its diverse presentations and the advanced age of most patients. The goals of therapy range from symptom management to, in rare cases, curative intent.

Treatment Option	Main Use/Indication	Curative?	Source
Supportive care	Anemia, infections, bleeding	No	1 2 12
Hypomethylating agents (HMA)	Intermediate/high-risk CMML, excess blasts	No	1 2 14 12
Hydroxyurea	Cytoreduction in proliferative CMML	No	2 12 14
Allogeneic stem cell transplant	Selected younger/high-risk patients	Yes (only option)	1 2 11 13
Novel/targeted therapies	Clinical trials, select molecular subtypes	No (in development)	1 2 14

Table 4: CMML Treatment Approaches

Current and Emerging Therapies

Supportive Care

• Most patients, especially those with lower-risk disease, benefit from supportive measures:
  • Red blood cell transfusions for anemia
  • Erythropoiesis-stimulating agents
  • Antibiotics for infections
  • Platelet transfusions for bleeding 1 2 12
• Supportive care aims to improve quality of life and manage symptoms, rather than cure the disease.

Hypomethylating Agents (HMAs)

• Drugs such as azacitidine and decitabine are standard for higher-risk patients or those with excess blasts 1 2 14.
  • They can improve blood counts, reduce symptoms, and delay progression—but responses are often temporary.
  • Recently, an oral formulation (decitabine/cedazuridine) provides a more convenient option 2.
• HMAs are not curative but can offer meaningful disease control.

Hydroxyurea

• Used mainly for proliferative CMML to reduce high white blood cell counts and manage splenomegaly 2 12 14.
• It is well-tolerated and can quickly relieve symptoms of cell overproduction.

Allogeneic Stem Cell Transplantation

• The only curative therapy for CMML, but rarely used due to patient age and co-morbidities 1 2 11 13.
  • Best suited for younger, otherwise healthy patients with high-risk disease.
  • Carries significant risks, including graft-versus-host disease and infection.

Novel and Targeted Therapies

• Ongoing research is evaluating targeted therapies (e.g., JAK inhibitors, IDH inhibitors, venetoclax, magrolimab, lenzilumab) 1 2 14.
  • Some, like ruxolitinib, can help reduce spleen size and constitutional symptoms 2.
  • None are yet approved specifically for CMML outside clinical trials.

Treatment Strategies

• Risk stratification guides treatment choices, with low-risk patients often observed or given supportive care, and high-risk patients considered for HMA therapy or transplant 2 13.
• Clinical trials are encouraged, especially for relapsed or refractory cases.

Conclusion

Chronic Myelomonocytic Leukemia is a uniquely challenging disease, blending features of both myelodysplastic and myeloproliferative disorders. Its clinical presentation, types, causes, and treatments are highly variable, necessitating individualized patient care.

Key takeaways:

• Symptoms range from fatigue and infections to splenomegaly and constitutional complaints, varying with disease severity 1 2 12.
• Types include myelodysplastic and myeloproliferative CMML, as well as emerging variants like oligomonocytic CMML 5 7 12.
• Causes are rooted in age-related clonal mutations, with TET2, SRSF2, and ASXL1 among the most frequently altered genes 3 8 9 10.
• Treatment is tailored by risk, with supportive care, HMAs, and hydroxyurea as mainstays, and stem cell transplant as the only curative option for a minority of patients; novel therapies are under investigation 1 2 11 14.

CMML management continues to evolve. Advances in our understanding of its underlying genetics and biology are paving the way for more targeted, effective, and individualized therapies. For now, multidisciplinary care and careful risk assessment remain the cornerstones of optimal patient outcomes.