Page 40 - Haematologica Vol. 110 - January 2025

REVIEW ARTICLE - Molecular pathogenesis and novel treatments for CMML L. Marando et al.
early phase clinical trials (NCT05549661). Combinations with other cell cycle checkpoint and DNA damage repair inhibitors remain to be explored. Additional targets of interest are outlined in Figures 4 and 5, with reported results in CMML cohorts summarized in Table 1.
Conclusion
Epigenetic dysregulation in CMML leads to myeloid bias and clonal monocytosis. Subsequent acquisition of epigenetic/ transcription factor mutations typically results in dysplastic CMML, whereas signaling mutations are more commonly associated with the more aggressive proliferative CMML.86 Increased activation of pro-inflammatory pathways in clonal monocytes as well as accumulation of leukemia-derived plas- macytoid dendritic cells, causing suppression of the adaptive immune system, drive more severe clinical manifestations with inferior outcomes. Despite active research, there remains
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an unmet clinical need to improve outcomes for CMML pa- tients. Single-agent therapy fails to alter disease biology and the complex pathophysiology of CMML highlights the need to explore combination strategies, with several clinical trials currently underway.
Disclosures
MMP has received research funding from Kura Oncology, Stem Line, Epigenetix, Polaris, and Solutherapeutics.
Contributions
LM, CMC and MMP reviewed existing data, wrote the man- uscript and prepared the Figures and Table.
Funding
This work was supported in part by funding from the NIH National Cancer Institute (R01CA272496) to MMP.
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