Clonal cytopenia of undetermined significance (CCUS)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
  • Recommendation:
    no
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
  • Recommendation:
    no
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

If an acquired mutation or chromosomal change is detected in patients with unexplained cytopenia and the absence of cytomorphological features of a myeloid disease, clonal cytopenia of undetermined significance (CCUS) is present (Steensma et al. 2015, Valent et al. 2017). Depending on the cytogenetic change observed, MDS of the category "MDS, unclassifiable" may also be present (CCUS, diagnostics, chromosome analysis).

Classification

Characteristics of CCUS
(Steensma et al. 2015, Bejar Leukemia et al. 2017, Greenberg et al. 2020)

  • Evidence of clonal haematopoiesis*

  • Absence of dysplasia of hematopoiesis in bone marrow

  • Persistent cytopenia

  • No proliferation of blasts in bone marrow/blood

*Detection of somatic mutations in genes associated with myeloid neoplasm with an allele frequency ≥ 2% and/or clonal chromosomal abnormality


Delineation from CHIP and MDS

Clonal cytopenia of indeterminate significance must be distinguished from clonal hematopoiesis of indeterminate potential (CHIP), in which acquired mutations or acquired chromosomal changes are also detectable but cytopenia is not present.

Furthermore, according to the WHO classification 2017, a distinction must be made between MDS and MDS of the category "MDS, unclassifiable" (MDS-U). This is diagnosed in the presence of persistent cytopenia, certain % limits of blasts in the peripheral blood/bone marrow and certain cytogenetic alterations (see CCUS, Diagnostics, Chromosome analysis) even in the absence of morphological features necessary for the diagnosis of MDS. Patients diagnosed with MDS that cannot be further classified should be carefully monitored for disease progression into a more specific MDS subtype.

Diagnostics

Prognosis

The study by Malcovati et al. shows that there is a highly predictive mutation pattern for myeloid neoplasm among patients with cytopenia (Blood 2017). These include, as mentioned above, mutations in spliceosome genes (SF3B1, SRSF2, U2AF1, ZRSR2), RUNX1 and JAK2 as well as mutations in ASXL1, DNMT3A and TET2, each in combination with at least one other mutation. The risk of progression of CCUS to myeloid disease was also investigated in this study: a risk of progression of approximately 20% per year was present in patients with cytopenia and the above-mentioned patterns. The detection of other mutations or constellations of mutations in persistent cytopenia also speaks for the presence of CCUS, but with a lower risk of progression into myeloid neoplasm (risk of progression of about 10% per year).

Figure 1: Differential diagnosis of unexplained cytopenia. If both myeloid neoplasms and reactive/secondary forms can be excluded as the cause of cytopenia, the diagnosis is cytopenia of uncertain significance (CUS). The detection of mutations is of prognostic relevance in this context. The risk of progression in patients with clonal cytopenia of indeterminate significance (CCUS) depends on the mutations or mutation patterns present.

Our own data from our laboratory (Baer et al. 2018) also confirm that mutations occur in 21% of patients without morphological abnormalities. This means that mutation diagnostics can provide valuable information both in the context of cytomorphologically/cytogenetically confirmed MDS and in the context of unexplained cytopenia.

Mutation detection therefore has either prognostic significance or an influence on the probability of developing myeloid neoplasm. If no mutation can be detected, the risk of developing a haematological disease is considered low.

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