Clonal cytopenia of undetermined significance (CCUS) with dysplasia is enriched for MDS‐type molecular findings compared to CCUS without dysplasia

Abstract

Objectives Although morphologic dysplasia is not typically considered a feature of CCUS, we have consistently observed low‐level bone marrow (BM) dysplasia among CCUS patients. We sought to determine whether sub‐diagnostic BM dysplasia in CCUS patients is associated with other clinico‐pathologic findings of myelodysplastic syndrome (MDS). Methods We identified 49 CCUS patients, 25 with sub‐diagnostic dysplasia (CCUS‐D), and 24 having no dysplasia (CCUS‐ND). We compared the clinical, histologic, and laboratory findings of CCUS‐D and CCUS‐ND patients to 49 MDS patients, including blood cell counts, BM morphology, flow cytometry, cytogenetics, and results of next‐generation sequencing. Results No statistically significant differences were observed between CCUS‐D and CCUS‐ND patients in the degree of cytopenias, BM cellularity, myeloid‐to‐erythroid ratio, or the presence of flow cytometric abnormalities. However, compared to CCUS‐ND, CCUS‐D patients exhibited increased mutations in myeloid malignancy‐associated genes, including non‐TET2/DNMT3A/ASXL1 variants, spliceosome (SF3B1, SRSF2, ZRSR2, or U2AF1) variants, and IDH2/RUNX1/CBL variants. CCUS‐D patients were also enriched for higher variant allele frequencies and co‐mutation of TET2/DNMT3A/ASXL1 with other genes. Conclusions CCUS‐D patients exhibit a molecular (but not clinical) profile more similar to MDS patients than CCUS‐ND, suggesting CCUS‐D may represent a more immediate precursor to MDS and may warrant closer clinical follow‐up.

Morphologic, immunophenotypic, and molecular genetic comparison study in patients with clonal cytopenia of undetermined significance, myelodysplastic syndrome, and acute myeloid leukemia with myelodysplasia‐related changes: A single institution experience

“…Both CCUS with sub‐diagnostic dysplasia and CCUS without dysplasia patients were reported to display significantly fewer MFC abnormalities compared with MDS patients 6 . Our current study was consistent with this finding.…”

“…One CCUS patient (#1) with mutations of SRSF2, TET2, NRAS, and Both CCUS with sub-diagnostic dysplasia and CCUS without dysplasia patients were reported to display significantly fewer MFC abnormalities compared with MDS patients. 6 Our current study was consistent with this finding. Dimopoulos et al showed that MFC had lower diagnostic sensitivity to differentiate patients with idiopathic cytopenia of undetermined significance from patients with CCUS.…”

“…Our study showed similar findings. Jajosky et al demonstrated CCUS patients with sub-diagnostic dysplasia were enriched with MDS-type of mutations compared with CCUS patients without dysplasia 6. All four cases of CCUS with mutation in splicing factors also showed <10% dysplasia in one-or two-cell lineage in our study.Our study showed MDS-EB and AML-MRC patients harbored significantly more somatic mutations in transcription factors compared with CCUS patients.…”

“…Limited number of multiparametric flow cytometry (MFC) studies have been performed in CCUS patients. [5][6][7] In our current study, we have evaluated morphologic changes, MFC abnormalities, and genomic alterations in CCUS patients and compared these findings in patients with MDS and AML with myelodysplasia-related changes (AML-MRC).…”

A comprehensive analysis of cytopenias and bone marrow morphology in patients with a history of bariatric and metabolic surgery

“…A recent report showed that the recognition of even slight dyspoietic changes (<10% of a cell lineage) in the absence of other factors known to cause myelodysplasia is closely associated with CCUS, and confers a higher risk of developing MDS, than CCUS without these findings. 24 Unspecified CCUS patients have an 80% risk of developing a myeloid malignancy within 5 years of diagnosis, 25 making the recognition of even slight dysplasia increasingly relevant even though its recognition poses a significant challenge for hematopathologists due to interobserver variability in practice as well as in this study. Patients with certain identifiable nutrient deficiencies such as copper deficiency, may also demonstrate bone marrow changes that closely mimic myelodysplasia.…”