Clonal Haematopoiesis and Progression to Myelodysplastic Syndrome in Patients with Unexplained Cytopenias

Abstract

A patient with unexplained cytopenia and no dysplasia used to be told there was nothing to find. Targeted sequencing now identifies a clone in a substantial minority of them, and the clone changes the answer: myeloid neoplasm becomes fourteen times more likely, and which mutations are present predicts how likely. Objectives: To review the published evidence on clonal haematopoiesis in patients investigated for unexplained cytopenia: how often a clone is found, what proportion progress to a myeloid neoplasm, over what timescale, which mutation patterns carry the risk, and what follows for surveillance. Material and Methods: Narrative review of prospective cohorts, sequencing studies, comparative analyses and consensus definitions indexed in PubMed and
the major haematology journals. Studies were eligible if they reported the prevalence, mutation profile or outcome of clonal haematopoiesis in a defined population investigated for cytopenia of unknown cause. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: Among patients investigated for unexplained cytopenia, 8 to 36 per cent are found to carry a clone at a variant allele frequency of 2 per cent or above without diagnostic dysplasia, meeting the definition of clonal cytopenia of undetermined significance. Myeloid neoplasm is approximately fourteen times more likely in that group than in patients whose cytopenia is non-clonal. In a prospective cohort of 400 such patients, 20 per cent developed a myeloid neoplasm within ten years, predominantly myelodysplastic syndrome (46 per cent of progressions) and overlap syndromes (32 per cent), and 84 per cent of all progressions occurred within the first five years. The number of mutated genes was the strongest single predictor. Spliceosome mutations, RUNX1 and JAK2 predict progression specifically, as does the combination of a DNA methylation gene mutation with at least one other lesion. Conclusion: Sequencing converts an undiagnosable presentation into a risk-stratified one, and the stratification is meaningful enough to guide surveillance interval. What it does not yet do is identify anyone who benefits from treatment before progression occurs. Abbreviations: CCUS – Clonal Cytopenia of Undetermined Significance, ICUS – Idiopathic Cytopenia of Undetermined Significance, CUS – Cytopenia of Undetermined Significance, CHIP – Clonal Haematopoiesis of Indeterminate Potential, CHRS – Clonal Haematopoiesis Risk Score, MDS – MyelodysplasticSyndrome, MPN –  Myeloproliferative Neoplasm, AML – Acute Myeloid Leukaemia, VAF – Variant Allele Frequency, NGS – Next-Generation Sequencing,
PPV – Positive Predictive Value.