More Than Just Monocytes
Imagine a disease that simultaneously possesses the characteristics of two different types of blood cancers, defying easy classification and challenging treatment paradigms. This is chronic myelomonocytic leukemia (CMML), a rare but aggressive hematologic malignancy that walks the line between myelodysplastic syndromes (ineffective blood cell production) and myeloproliferative neoplasms (excessive blood cell production). With an incidence of less than 1 case per 100,000 people annually, CMML is considered a rare disease, yet its impact is profound 1 .
<1 per 100,000 annually
15-20% within 3-5 years
Over 70 years
>95% of patients
The clinical journey of CMML patients is particularly challenging—approximately 15-20% will transform to acute myeloid leukemia (AML) within 3-5 years of diagnosis, making it one of the most unpredictable myeloid malignancies 4 7 . What makes CMML especially relevant in today's aging society is its striking predilection for older adults, with a median age at diagnosis of over 70 years 4 .
Chronic myelomonocytic leukemia is a clonal hematopoietic stem cell disorder characterized by sustained peripheral blood monocytosis (increased monocyte counts) and bone marrow dysplasia (abnormal development of blood cells) 1 7 . The World Health Organization (WHO) and International Consensus Classification (ICC) have established specific diagnostic criteria, including:
The pathogenesis of CMML is deeply rooted in age-related clonal hematopoiesis, where hematopoietic stem cells accumulate mutations over time 4 . By age 70, most blood cells are derived from only 10-20 stem cell clones, some of which carry cancer-driving mutations 4 . More than 95% of CMML patients harbor somatic mutations, with specific patterns influencing disease behavior and prognosis 1 7 .
∼60-90% of cases
Mutations in genes like TET2 (∼60%), ASXL1 (∼40%), and DNMT3A disrupt normal chemical modifications that control gene expression.
∼50% of cases
Mutations in SRSF2 affect how messenger RNA is processed, leading to abnormal protein production.
∼30% of cases
Mutations in RAS pathway genes (NRAS, KRAS, CBL, NF1) are associated with proliferative phenotype.
| Gene | Frequency | Functional Category | Clinical Significance |
|---|---|---|---|
| TET2 | ∼60% | Epigenetic regulator | Often ancestral mutation; better prognosis when sole mutation |
| SRSF2 | ∼50% | RNA splicing | Frequently co-occurs with TET2 mutations |
| ASXL1 | ∼40% | Chromatin modification | Truncating mutations predict inferior outcomes |
| RAS Pathway | ∼30% | Cell signaling | Associated with proliferative phenotype and AML transformation |
Diagnosing CMML requires a multifaceted approach that goes beyond simple blood counts. The current diagnostic workflow includes:
Reveals persistent monocytosis (≥0.5 × 10⁹/L) and may show other abnormalities like anemia or thrombocytopenia 1 7 .
Assesses cellularity, dysplasia, fibrosis, and blast percentage (must be <20%) 1 .
Identifies chromosomal abnormalities present in approximately 30% of patients 7 .
Recent research has highlighted the importance of immature granulocytes (iGRANs) in CMML progression. These cells not only belong to the malignant clone but also function as immunosuppressive cells that promote disease progression by suppressing the immune system's ability to fight the cancer 3 . A 2025 study published detailed a sophisticated flow cytometry protocol to quantify these cells, providing clinicians with both diagnostic and prognostic tools 3 .
This protocol allows for both relative quantification (iGRANs as a fraction of myeloid cells) and absolute quantification (absolute iGRAN count per volume of blood) 3 . The accumulation of these immunosuppressive cells in peripheral blood correlates with poor outcomes, similar to observations in solid tumors and severe sepsis 3 . This method provides clinicians with a valuable tool for patient stratification and monitoring treatment response.
| Reagent | Specific Example | Function in Experiment |
|---|---|---|
| Antibody Panel | APC anti-human CD56, FITC anti-human CD66b, Percp5.5 anti-human CD11b, etc. | Cell surface staining for population identification |
| Density Gradient Medium | Ficoll solution (density 1.077 g/mL) | Separation of mononuclear cells from whole blood |
| Staining Buffer | PBS with fetal bovine serum | Provides medium for antibody staining |
| Hemolytic Solution | Ammonium chloride-based | Lyses residual red blood cells after separation |
| Flow Cytometer | Fortessa cytometer (5 lasers) | Cell analysis and data acquisition |
The treatment arsenal for CMML remains limited, with approaches tailored to individual patient factors including disease subtype, risk stratification, and eligibility for intensive therapy.
The only potentially curative option for CMML, but limited by patient age and comorbidities given the typical diagnosis age >70 years 1 7 .
Azacitidine and decitabine are the only FDA-approved drug therapies for CMML. These drugs work by reversing abnormal DNA methylation patterns, potentially reprogramming cancer cells 6 7 . However, their effectiveness is limited, particularly in proliferative subtypes with RAS mutations 6 .
A chemotherapy drug that can help control blood counts, particularly in proliferative CMML, and may extend survival for some patients 6 7 .
The CMML therapeutic pipeline is remarkably active, with over 20 companies developing more than 25 investigative candidates 2 . Promising approaches include:
IO-202, a first-in-class monoclonal antibody targeting LILRB4 (a receptor highly expressed on CMML cells), has received FDA fast-track designation and is in Phase I/II trials 6 .
Timdarpacept, a recombinant SIRPα fusion protein that blocks the "don't eat me" signal to immune cells, is in Phase III development 2 .
The PREACH-M trial investigating azacitidine with lenzilumab (an antibody against GM-CSF) has shown remarkable early results 5 .
The PREACH-M trial represents one of the most promising recent developments in CMML treatment. This Australian study, led by Associate Professor Dan Thomas, combines the standard therapy azacitidine with the investigational antibody lenzilumab 5 .
Interim results published in Blood journal demonstrated 5 :
Associate Professor Thomas captured the significance of these findings: "Not only are patients experiencing short-term improvements in their blood counts and symptoms; they're maintaining those improvements for years. That's something we haven't been able to achieve before" 5 .
The success of this combination therapy suggests that simultaneously targeting the malignant clone (with azacitidine) and the inflammatory microenvironment (with lenzilumab) may provide synergistic benefits for CMML patients.
The landscape of CMML research and treatment is rapidly evolving. Beyond the therapies mentioned, investigators are exploring CAR-T cell therapies, JAK inhibitors, and various combination regimens to improve outcomes 8 . The global CMML market is poised for significant growth as these innovative approaches mature, driven by increasing disease recognition in aging populations and advances in personalized medicine 8 .
The integration of digital health technologies, such as remote monitoring and telemedicine, may further enhance long-term disease management for CMML patients 8 .
The development of companion diagnostics like liquid biopsies and next-generation sequencing is enabling more accurate diagnosis and personalized treatment plans 8 .
In conclusion, while CMML remains a challenging dual-natured malignancy, the growing understanding of its molecular foundations, combined with innovative therapeutic strategies, is transforming the outlook for patients. From sophisticated diagnostic tools like iGRAN quantification to groundbreaking clinical trials like PREACH-M, the future of CMML management is increasingly promising, offering hope for more effective and targeted treatments in the years to come.