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.