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Cytopenias and myeloid gene mutation

From www.haematologyetc.co.uk


What do the acronyms stand for?


CHIP: clonal haematopoiesis of indeterminate potential

ICUS: idiopathic cytopenias of uncertain significance

CCUS: clonal cytopenias of uncertain significance (generally divided into low and high risk)


Are these definitions important? - Yes, the different disorders carry different prognostic implications (see figure and table below)


CCUS ICUS.png A graph showing the risk of progression for the different disorders



A table of definitions and advice (also see notes)



CHIP
  • Patients have normal blood counts, and no features diagnostic of a myeloid disorder, but with ≥ 1 somatic mutation on myeloid panel
  • There is a 0.5-1% risk of progression to myeloid disorder each year
  • Consider follow-up blood counts (possibly in primary care) and repeat myeloid panel and assessment if change in FBC



ICUS
  • Cytopenia of unclear significance i.e. lacking other features that directly suggest a myeloid disorder
  • No diagnostic morphological features of myeloid disorder
  • No somatic mutations detected on the myeloid gene panel
  • There is a low risk of progression to myeloid neoplasm (approximately 10% at 5 years)
  • Follow-up with PB counts (possibly in primary care); repeat myeloid panel only if change in FBC



CCUS low risk
  • Morphological features not diagnostic of a myeloid disorder, but a cytopenia is present in one or more lineages without an identifiable alternative cause
  • One somatic mutation found on myeloid panel (this should not be ‘high risk’ mutations)
  • There is an Intermediate risk of progression to myeloid neoplasm (approx. 55% 5 year risk)
  • Advise follow up using blood counts and repeat myeloid panel if significant change in condition



CCUS high risk
  • Clinical and morphological features are not diagnostic of a myeloid disorder, but cytopenia is found in one or more lineages without an identifiable alternative cause
  • There is one or more "high risk" mutations detected on myeloid panel or there are two or more concurrent mutations of ‘non high risk’ genes
  • This has the highest risk of progression to myeloid neoplasm with (approx. 95% 5 year risk)
  • Follow up is advised as per low risk MDS patients



High-risk mutations: these indicate a high predictive value for developing myeloid neoplasms

  • Any Spliceosome gene mutation (SF3B1, SRSF2, U2AF1 or RUNX1)
  • Presence of two or more mutations
  • Two mutations still being evaluated may indicate high risk, but not at present: JAK2, p53


Important Notes

Before applying the definitions below please be aware of these points:

  • Is your patient young? - CHIP is very rare in younger age groups, so these definitions should not be applied in patients younger than 40 years and should be used with caution in those <50years.
  • What is the "VAF"? - The proportion of cells expressing the mutation is important. This is indicated by the variant allele frequency (VAF) which should be less than 10% for CHIP mutations.
  • Are there any high risk gene mutations? - Mutations affecting particular genes or simultaneously affecting several different genes may place individuals in high-risk categories irrespective of other features (see below)
  • Should you perform a cytogenetic evaluation? -. A cytogenetic lesion is uncommon in the absence of a molecular lesion (1.5%). This analysis will not be performed routinely, but in difficult cases can be activated on clinician request.
  • Are there other implications to the diagnosis? - Possibly, patients with clonal haemtopoiesis are frequently more frail and may carry an increased risk of other disease, however this is (as yet) poorly defined.

Sources


1. Click here for a useful educational page from ASCO

2. Review from blood