Page 37 - Haematologica Vol. 110 - January 2025

REVIEW ARTICLE - Molecular pathogenesis and novel treatments for CMML L. Marando et al.
Likewise, mutations affecting pre-mRNA splicing, including SRSF2 mutations, have also been shown to result in the hyperactivation of nuclear factor-KB signaling pathways.78,79 The presence of clonal myeloid cells is therefore likely to sustain a “vicious circle” of inflammation and clonal expan- sion in which an inflammatory milieu confers a selective advantage to the mutant clone, while at the same time, the mutant clone is able to perpetuate inflammation. Further underscoring this concept, autocrine or paracrine activation of MAPK though C-C chemokine receptor type 2 (CCR2) has been implicated in defective apoptosis of circulating classical monocytes in CMML.80
The progression of chronic myelomonocytic leukemia to acute myeloid leukemia
Rates of progression to secondary AML remain high,2 with current survival outcomes after blast transformation remaining dismal (median overall survival, <9 months).2 Acquisition of additional somatic driver mutations in the coding DNA, or increments in variant allele fraction of existing driver mutations, explain transformation in only 40-60% of patients.38,81 Mutations in the non-coding ge- nome, somatic copy number alterations, and epigenetic mechanisms, likely in the context of reduced immune surveillance, emerge as plausible mechanisms that need to be explored. Understanding steps that lead to AML transformation is a much-needed area of research, and a critical one to improve outcomes in patients.
Contemporary therapeutic approaches for chronic myelomonocytic leukemia
Allogeneic hematopoietic stem cell transplant is the only potential cure for CMML; however, due to older age and comorbidities, this approach is unfeasible for the majority of patients. DNA methyltransferase (DNMT) inhibitors, also referred to as hypomethylating agents, remain the only Food and Drug Administration-approved treatment options for CMML, but overall response rates are <50%, with true remissions being achieved in <20% patients.82,83 In a large multicenter study, we showed that the best predictor of response to DNMT inhibitors is the presence of TET2 mutations in the absence of ASXL1 mutations.84 Although use of DNMT inhibitors can lead to demethyl- ation at promoters and CpG islands,83 response to these inhibitors occurs in the absence of significant variation in the clonal structure.85 Several studies have shown a lack of correlation between differences in promoter meth-
ylation and transcriptional changes in CMML,37,38 a phe- nomenon that might explain why, despite an epigenetic effect, DNMT inhibitors do not affect the mutant allelic burdens, nor alter the natural history of the disease.86 Ascorbic acid is an important cofactor for TET dioxygenase activity, prompting the use of parenteral ascorbic acid in combination with DNMT inhibitors in TET2-mutant CMML. In this setting, ascorbic acid has been postulated to enhance TET2 activity generated from the unmutated allele and/or exploit functional redundancies with TET3 in the hematopoietic system.87
The synergistic effect of venetoclax and 5-azacitidine is much less pronounced in CMML than in AML.88,89 Some mechanistic insights come from studies in AML patients. Monocytic and/or RAS-mutated AML is more resistant to BCL2 inhibition, and thus venetoclax can favor the outgrowth of monocytic subpopulations that arise from low variant allele fraction NRAS-mutated and KRAS-mu- tated clones. These clones activate an MLL-specific leukemia stem cell signature and show dependency on the anti-apoptotic protein MCL-1.90 CMML monocytes too show dependency on MCL-1, resulting in defective apoptosis, with a combination of MCL1 and MEK inhibitors showing early promise in xenografts models.80 Although, traditionally, the RAS/RAF/MEK/ERK pathway has been difficult to target in hematologic malignancies due to the lack of effective drugs and the late and subclonal nature of its mutations, CMML is an exception, given that in proliferative CMML, RAS mutations are often early and dominant clonal events.38 Novel RAS-directed therapies including the on and off KRAS G12C and G12D inhibitors and the pan-RAS GTPase inhibitors can play an important role in the management of proliferative CMML,91,92 and can inform safety and dosing in myeloid neoplasms, in which RAS mutations play a role in disease progression and contribute to resistance to FLT3, IDH1, IDH2, and BCL2 inhibitors.
Inhibition of the RAS-activated PI3K pathway is an en- ticing yet underexplored approach in CMML. As dual MAPK/PI3K pathway inhibition resulted in dose-limiting toxicities in solid tumors,52 other combinatorial strategies are needed. For example, the combination of the PI3Kd inhibitor, umbralisib, and the JAK1/2 inhibitor, ruxolitinib, was synergistic in pre-clinical colony-forming assays using primary CMML samples.93 This combination has since entered early phase clinical trials (NCT02493530). Moreover, in addition to their impact on methylation, DNMT inhibitors form covalent DNA-DNMT1 adducts that invoke an ATR-CHK1-mediated DNA damage response.94-96 Thus, combinations of DNMT inhibitors with inhibitors of cell cycle checkpoints are of particular interest. Specifically, polo-like kinase 1 (PLK1) is upregulated in RAS-mutated proliferative CMML and PLK1 inhibition was efficacious in patient-derived xenograft models of proliferative CMML.38 Accordingly, the PLK1 inhibitor, onvansertib, has entered
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