The use of targeted sequencing and flow cytometry to identify patients with a clinically significant monocytosis.

The diagnosis of chronic myelomonocytic leukemia (CMML) remains centered on morphology, meaning that the distinction from a reactive monocytosis is challenging. Mutational analysis and immunophenotyping have been proposed as potential tools for diagnosis; however, they have not been formally assessed in combination. We aimed to investigate the clinical utility of these technologies by performing targeted sequencing, in parallel with current gold standard techniques, on consecutive samples referred for investigation of monocytosis over a 2-year period (N = 283). Results were correlated with the morphological diagnosis and objective outcome measures, including overall survival (OS) and longitudinal blood counts. Somatic mutations were detected in 79% of patients, being invariably identified in those with a confirmed diagnosis (99%) but also in 57% of patients with nondiagnostic bone marrow features. The OS in nondiagnostic mutated patients was indistinguishable from those with CMML ( = .118) and significantly worse than in unmutated patients ( = .0002). On multivariate analysis, age, ASXL1, CBL, DNMT3A, NRAS, and RUNX1 mutations retained significance. Furthermore, the presence of a mutation was associated with a progressive decrease in hemoglobin/platelet levels and increasing monocyte counts compared with mutation-negative patients. Of note, the immunophenotypic features of nondiagnostic mutated patients were comparable to CMML patients, and the presence of aberrant CD56 was highly specific for detecting a mutation. Overall, somatic mutations are detected at high frequency in patients referred with a monocytosis, irrespective of diagnosis. In those without a World Health Organization-defined diagnosis, the mutation spectrum, immunophenotypic features, and OS are indistinguishable from CMML patients, and these patients should be managed as such.