Abstract Body

The term of Clonal Cytopenia of Undetermined Significance (CCUS) has been introduced for describing a condition characterized by persistent cytopenia not caused by another comorbid condition and a somatic mutation in a myeloid neoplasm (MN) driver gene [Steensma et al. Blood 2015]. CCUS has been recognized as pre-malignant disorder by the recent proposals for the revision of the classification of MNs [Arber et al. Blood 2022; Khoury et al. Leukemia 2022].

Prospective studies showed that the risk of progression into MN is affected by clone features, including the number and type of driver mutations and the clone size [Malcovati et al. Blood 2017]. Unsupervised analyses based on mutation profiles identified distinct clusters of patients with CCUS, showing different survival and risk of progression into MN. Notably, subjects with selected clone metrics showed survival and risk of disease progression not dissimilar to those with MN, supporting the notion that a fraction of CCUS may represent an early manifestation of a MN rather than a pre-malignant condition [Gallì et al. Blood 2021]. Recently, genetic mutations and laboratory values have been combined to define a clonal hematopoiesis risk score (CHRS), which provides simple prognostic framework to distinguish subjects at high risk for progression to MN [Weeks et al. Blood 2022].

The clinical context appears to be relevant in shaping the evolutionary trajectories of these disorders. Patients developing CCUS after exposure to chemoradiotherapy for non-myeloid tumors are at higher risk of developing a therapy-related MN, while the significance of clonal cytopenia in patients treated for acute myeloid leukemia warrants interpretation with respect to minimal/measurable residual disease. A recent study in chronic idiopathic neutropenia reported a biased distribution of CH, associated with high relative risk for transformation into MN [Tsaknakis et al. Blood. 2021].

In cases with persistent mild monocytosis, evidence of CH but indeterminate bone marrow features, the definition of clonal monocytosis of undetermined significance (CMUS) has been proposed. Consistently, monocytosis (≥10% and ≥0.5x10⁹/L of the WBC) almost invariably segregated precursor conditions with potential to progress to MDS/MPN [Cargo et al. Blood 2019; Gallì et al. Blood 2021].

The association of cytopenia and CH can be observed in other disorders that are to be distinguished from CCUS. These include aplastic anemia with CH, paroxysmal nocturnal hemoglobinuria, or VEXAS syndrome. In addition, CH can be an incidental finding in well-established cytopenias of other origin, with uncertain clinical implications.

References

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Tsaknakis et al. Incidence and prognosis of clonal hematopoiesis in patients with chronic idiopathic neutropenia. Blood. 2021 Oct 7;138(14):1249-1257.

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