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)

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