Chronic myelomonocytic leukemia: at the molecular roots of inflammation

By Lila Rouland | Published September 22, 2025 | 3 min read


#Hematology #ChronicLymphocyticLeukemia  


Chronic myelomonocytic leukemia (CMML) is a rare clonal hematologic disorder that lies at the crossroads between myelodysplastic syndromes and myeloproliferative neoplasms. It occurs mainly in older adults (median age >70 years) and is characterized by persistent monocytosis and a high risk (15–20% at 5 years) of transformation into acute myeloid leukemia (AML). Clinically, two forms are distinguished:

• Dysplastic form (dCMML): dominated by cytopenias and a relatively slow course.
• Proliferative form (pCMML): marked by RAS mutations, splenomegaly, and shorter survival (18–24 months versus 45–60 months for dCMML).

At the heart of pathogenesis, aging of hematopoietic stem cells promotes the accumulation of mutations (TET2, ASXL1, SRSF2, RAS), which disrupt the balance between differentiation and inflammation. Highly inflammatory clonal monocytes explain the association with autoimmune diseases and increased cardiovascular risk. Plasmacytoid dendritic cells, often expressing CD123 and IDO, contribute to immune tolerance and leukemic progression.

Target, combine, innovate: the new era of treatment

The only potentially curative therapy remains allogeneic stem cell transplantation, which is rarely available to elderly patients. In practice, hypomethylating agents (azacitidine, decitabine) remain the standard, but with modest results (<50% response rate, <20% complete remissions). TET2 mutations (without ASXL1) are associated with better responses.

In light of these limitations, several new avenues are emerging:

• Epigenetics: ascorbate to restore TET2 activity, HDAC inhibitors.
• Signaling pathways: MEK inhibitors (trametinib), novel molecules targeting KRAS or pan-RAS GTPases.
• Inflammation and microenvironment: lenzilumab (anti–GM-CSF) with promising results in the PREACH-M trial (55% complete remissions); ruxolitinib (anti–JAK2) for GM-CSF–sensitive forms; canakinumab (anti–IL-1β) and NLRP3 inhibitors to block the inflammatory loop.
• Immunologic targeting: tagraxofusp directed against CD123 to prevent AML transformation; sabatolimab (anti–TIM-3) explored in combination with hypomethylating agents.
• Apoptosis: venetoclax, effective in AML, shows reduced activity in CMML due to resistance of monocytic clones.

A future still to be built

CMML arises from the interplay of founding mutations (TET2, SRSF2, ASXL1), activation of signaling pathways (RAS), and immuno-inflammatory deregulation, leading to clonal monocytosis and variable progression toward AML.

Current treatments (hypomethylating agents) remain limited, and allogeneic transplantation is rarely feasible.

The therapeutic future lies in combined strategies targeting signaling pathways, the epigenome, and immunity, with the goal of truly modifying disease biology and improving prognosis. 

Read next: CMML: finally a target in sight?

About the author – Lila Rouland
With dual expertise in science and marketing, Lila brings her knowledge to the service of healthcare innovation. After five years in international academic research, she transitioned into medical and scientific communication within the pharmaceutical industry. Now working as a medical writer and content developer, she is committed to highlighting scientific knowledge and conveying it to healthcare professionals with clarity and relevance.