The utility of novel technologies in the diagnosis of chronic myeloid malignancies

The approach to diagnosing the myelodysplastic syndromes (MDS) and
myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is primarily based on a
subjective morphological assessment that is neither sensitive nor specific.
Objective measures such as a cytogenetic assessment yield results in only a
proportion of patients. Over the past 2 decades a range of new technologies have
been developed which have the potential to revolutionise the diagnosis of these
conditions by providing an objective measure of disease.
This research aimed to investigate the utility of novel technologies in the diagnosis
of MDS and MDS/MPN overlap syndromes, in particular chronic myelomonocytic
leukaemia (CMML). The technologies utilized throughout the research included
flow cytometry, single nucleotide polymorphism (SNP) arrays and high throughput
sequencing (HTS). With the latter, a novel HTS panel was designed to target genes
commonly mutated in myeloid malignancies. This was initially used to investigate a
cohort of patients in whom a diagnosis could not be reached on initial analysis but
subsequently developed a myeloid malignancy. Somatic mutations were detected
at a very high frequency in the pre-diagnostic sample suggesting that targeted
sequencing, in particular, could confirm clonality. This technology was further
investigated on large cohorts of patients presenting with a monocytosis or
cytopenia in whom mutations correlated strongly with survival and blood count
trajectories as well as being predictive of a subsequent diagnosis.
The detection of somatic mutations in those with persistent monocytosis or
cytopenia, particularly with a clone size >20% and co-occuring mutations, is
clinically important and patients should be managed as per those with confirmed
disease. HTS is therefore essential in the diagnosis of these patients. This does
however raise concerns regarding funding and change management and will likely
necessitate rationalization of the diagnostic service. Overall, there is significant
potential to transform the diagnostic approach to this group of disorders.