Cytopenias and myeloid gene mutation
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)
A graph showing the risk of progression for the different disorders
A table of definitions and advice (also see notes)
- 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
- 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
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.