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
Doctor of Oncology, specialized in Biotechnology and Management
