Page 30 - Haematologica Vol. 110 - January 2025

REVIEW ARTICLE
Chronic myelomonocytic leukemia: molecular pathogenesis and therapeutic innovations
Ludovica Marando, Clifford M. Csizmar and Mrinal M. Patnaik
Division of Hematology, Department of Internal Medicine, Mayo Clinic, MN, USA.
Abstract
Chronic myelomonocytic leukemia (CMML) is an aggressive clonal stem cell disorder categorized among myelodysplastic/ myeloproliferative overlap neoplasms. While sharing features with both myelodysplastic syndromes and myeloproliferative neoplasms, CMML has distinct molecular and clinical profiles. The presence of CMML-specific prognostic models, response criteria, and dedicated clinical trials underscores a unique and complex biology. Age-related changes affecting the bone marrow microenvironment, immune responses, and the intricate balance between epigenetic deregulation and proinflam- matory signaling are characteristic of this disease, collectively posing significant scientific and clinical challenges in its management. CMML is an aging-related, clinically heterogeneous neoplasm with limited approved therapeutic options, representing an area of unmet medical need. This review offers a comprehensive analysis of the current understanding of the molecular mechanisms driving CMML evolution and its clinical manifestations within the ever-evolving landscape of precision medicine. In light of the most recent molecular discoveries, we highlight the shortcomings of existing therapies and underscore promising investigational agents. Many of the biological findings discussed are shared across a spectrum of acute and chronic myeloid neoplasms, as well as clonal hematopoiesis, broadening the scope of this review.
Correspondence: L. Marando Marando.Ludovica@mayo.edu
M.M. Patnaik
Patnaik.Mrinal@mayo.edu
Received: Accepted: Early view:
June 12, 2024. October 4, 2024. October 17, 2024.
https://doi.org/10.3324/haematol.2024.286061
©2025 Ferrata Storti Foundation Published under a CC BY-NC license
Aging and myeloid malignancies
In addition to sustained peripheral blood monocytosis and bone marrow dysplasia1 (Figure 1), CMML is associated with an inherent risk of transformation to secondary acute my- eloid leukemia (AML) of about 15-20% over 3 to 5 years.2 Like patients with AML, patients with CMML have about 10-15 mutations per kilobase of coding DNA. Although this is several-fold lower than in other malignancies (melanoma ~1,000, lung cancer ~150),3,4 CMML has a very heterogeneous clinical course.4 While only ASXL1 mutations reproducibly pre- dict inferior outcomes in CMML,5 higher levels of interleukin (IL)-10 (human cytokine synthesis inhibitory factor) have also been shown to improve prognosis,6 emphasizing a complex pathophysiology that extends beyond somatic alterations, including cytokine diversity and epigenetic deregulation.6 Among all hematologic neoplasms, CMML displays the most striking skewing towards older age with a median age at presentation of >70 years.1,2 Aging hematopoietic
stem cells (HSC) steadily accumulate mutations (mean of 17 per year after birth).7 While most are inconsequential, between one in 34 and one in 12 non-synonymous muta- tions provide a selective advantage and drive clonal expan- sion by cell-intrinsic and extrinsic selection pressures.7,8 Driver mutations commonly occur in leukemia genes, and lead to clonal hematopoiesis of indeterminate potential (CHIP) when such mutations can be detected at a variant allele fraction of ≥2%, in the absence of blood count ab- normalities. There is significant overlap between clonal hematopoiesis mutations and CMML driver mutations, with the majority of CMML patients showing mutations in ≥2 clonal hematopoiesis-associated genes (e.g., ASXL1, TET2, SRSF2). This suggests that in most cases, CMML develops on the background of age-related clonal hematopoiesis, with subsequent mutations shaping the CMML phenotype and AML transformation rates.9
Oxidative stress, telomere shortening, and activation of tumor suppressor genes all contribute to an abrupt re-
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