Clonal cytopenia of undetermined significance (CCUS)

With the 5th edition, clonal cytopenia of undetermined significance is listed for the first time in the WHO classification, and it is included among the myeloid precursor diseases (WHO 2022).

*Detection of one or more chromosomal aberrations resp. of one or more somatic mutations with an allele frequency of ≥2% (or ≥4% for X-linked gene mutations in males) (see Molecular Genetics, Table 1):

Clonal cytopenia of indeterminate significance should be distinguished from clonal hematopoiesis of indeterminate potential (CHIP), in which acquired molecular genetic alterations are detectable but cytopenia is not present.

CCUS and myelodysplastic neoplasm (MDS) have cytopenia(s) and clonal alterations in common. However, in CCUS the diagnostic criteria for classification according to WHO 2022 into the MDS subgroups "MDS with defining genetic alterations" or "MDS, morphologically defined" are not met.

Further information on MDS and MDS diagnostics can be found here.

Already the detection or exclusion of clonality has prognostic relevance and utility for differential diagnosis. If no mutation can be detected, the probability of diagnosing a myeloid neoplasia at the time of examination or during follow-up is low (high negative predictive value) (Malcovati et al. 2017, Shanmugam et al. 2019, Rossi et al. 2021).

Clonal hematopoiesis is associated with an increased likelihood that a hematologic neoplasia will exist or occur later in life. The positive predictive value for the presence of myeloid neoplasia can be maximized when a higher allele frequency (≥10% or ≥20%) and/or the presence of ≥2 gene mutations are applied as criteria (Malcovati et al. 2017, Shanmugam et al. 2019, Zheng et al. 2019, Galli et al. 2021). Certain mutations are also predictive of MDS - these include, in particular, mutations in spliceosome factors (SF3B1, SRSF2, U2AF1, ZRSR2) (Malcovati et al. 2017, Shanmugam et al. 2019, Galli et al. 2021) or RUNX1 and JAK2 (Malcovati et al. 2017). If DNMT3A, TET2, or ASXL1 mutations are present in combination with at least one other mutation, this mutation pattern is also predictive of MDS (Malcovati et al. 2017, Galli et al. 2021). A study on the significance of clonal hematopoiesis in individuals ≥80 years of age showed that overall survival of individuals with unclear cytopenia in combination with specific mutations is not different from patients with diagnosed myeloid neoplasia (Rossi et al. 2021).

The study by Malcovati et al. (2017) showed a risk of progression to myeloid neoplasia of approximately 20% per year for patients with cytopenia and the specific mutation patterns mentioned above. Detection of other mutations or mutational constellations in persistent cytopenia was associated with a lower risk of progression to myeloid neoplasia (progression risk of approximately 10% per year). Galli et al (2021) found an association of mutations in DTA genes (DNMT3A, TET2, ASXL1) and SF3B1 or TP53 and additional mutations with myelodysplasias already at an allele frequency of <20%. In contrast, mutation patterns involving SRSF2, isolated or multiple DTA mutations, or other multiple mutations were associated with dysplasias only at allele frequencies >30%.

In a prospective long-term study, 20% of the 400 CCUS patients developed a myeloid neoplasm after 10 years, predominantly MDS (46%) and MDS/MPN overlap syndromes (32%). 84% of all progressions occurred within the first five years after diagnosis. In the progression analysis, the number of mutated genes proved to be the strongest predictor (Cargo et al. 2025).

If the individual risk of progression (cf. also Prognosis) is strongly increased, especially in the case of one or more mutations with an allele frequency ≥10% or the presence of ≥2 mutations, quarterly monitoring by differential blood count is recommended with regard to progression to a hematologic neoplasm. In cases with a lower risk of progression, the recommendation is quarterly monitoring in the first year and annual monitoring from the second year onwards (Haferlach & Heuser 2022, see also Figure 2). In addition, based on the National MDS Study for CCUS, DeZern et al. recommend monitoring with 2–4 peripheral blood tests per year, annual to 1.5-yearly molecular tests (NGS), and bone marrow biopsies performed approximately every two years. These intervals may be shortened, for example, in cases of mutations with increased progression rates (DeZern et al. 2026).