Monoclonal B-cell lymphocytosis (MBL), chronic lymphocytic leukemia (CLL) precursor condition with an incidence of up to 12% in the elderly, precedes CLL; nevertheless, the duration of MBL and the mechanisms of its progression to CLL were mainly unclear. The B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples obtained up to 22 years before diagnosis was sequenced in this work. 

Even before the onset of lymphocytosis and regardless of the clonotypic IGH variable gene somatic hypermutation status, significant skewing in the BcR IGH gene repertoire was found in most patients. Furthermore, researchers found dominant clonotypes belonging to largely stereotyped subcategories associated with poor prognosis in 14 patients with CLL up to 16 years before diagnosis. 

The skewing of the BcR IGH gene repertoire rose considerably with time until a diagnosis or remained constant at high levels in 22 patients with longitudinal data. The CLL clonotype was already present in the prediagnostic samples for 14 of 16 patients with available samples at diagnosis. 

Overall, the findings suggested that the preclinical period of CLL might be more extended than previously assumed, even in patients with a poor prognosis.