By Ana Espino | Published on september 22, 2025 | 3 min read
#Leukemia #CMML #CD123 #Tagraxofusp
Chronic myelomonocytic leukemia
(CMML) is a rare and aggressive malignant blood disorder, characterized by
clonal proliferation of monocytes and marked clinical heterogeneity. It mainly
affects older individuals, carries a
high risk of transformation into acute
myeloid leukemia, and remains associated with
limited median survival.
Current treatments, mainly based on
hypomethylating agents such as
azacitidine or
decitabine, induce only
partial
and temporary responses, without significantly altering the natural history of
the disease. To date,
no targeted therapy has been approved for this
indication, despite improved understanding of molecular profiles. A major
challenge in the management of this condition therefore lies in developing
innovative therapeutic strategies capable of selectively targeting leukemic
cells without impairing normal hematopoiesis. Among the avenues being explored,
CD123, which is overexpressed in most CMML cases, represents a
promising
target.
With this in mind, a study was
launched to evaluate the
efficacy and tolerability of tagraxofusp, a
CD123-targeting immunotoxin, in patients with CMML.
Tagraxofusp: promise or just a
threshold effect?
Fourteen patients with CMML were
enrolled in this study, selected according to their exposure to
tagraxofusp
(
monotherapy at the standard dose of
12 mcg/kg/day for 5 days). Most had
advanced disease, with
prior treatments in
71% of cases, reflecting a heavily
pretreated population.
Clinically, the responses observed
included a
reduction in circulating monocytes,
stabilization of hematologic
parameters, and, in some patients,
partial improvement in the overall response
score. Two patients showed a significant decrease in bone marrow infiltration,
while another achieved a partial complete remission, indicating notable
antitumor activity in some cases.
The tolerability profile was
generally acceptable. As expected,
hepatic toxicities and
episodes of capillary
leak syndrome were reported in some patients, but without major complications.
These results suggest
interesting therapeutic potential for tagraxofusp in this
indication, which still lacks validated targeted options.
CD123 opens the path to targeted
therapy in CMML
CMML is a rare and aggressive blood
disorder, and its management remains particularly challenging after
failure of
hypomethylating agents. The main therapeutic hurdle is the lack of
effective
targeted treatments, despite the identification of relevant molecular targets.
In this context, this study aimed to
evaluate the benefit of
tagraxofusp, a
CD123-targeting immunotoxin, in a
population of heavily pretreated patients. The results suggest
moderate
antileukemic activity and
overall acceptable tolerability, with clinical
responses observed in some patients.
However, this study has several
limitations, including the
small sample size, lack of a comparison group, and
a
follow-up period too short to draw definitive conclusions. Larger, controlled
trials—especially those combining tagraxofusp with standard treatments such as
azacitidine—are needed. Targeting CD123 remains a promising approach,
particularly in the setting of combined and personalized strategies for this
disease, which still has no validated targeted therapy.
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About the author – Ana EspinoPhD in Immunology, specialized in Virology
