HIGH-RISK SUBTYPES OF CHRONIC LYMPHOCYTIC LEUKEMIA ARE DETECTABLE AS EARLY AS 16 YEARS BEFORE DIAGNOSIS

Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals. However, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor immunoglobulin heavy chain (BcR IGH) gene repertoire of 124 CLL patients and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, in 14 CLL patients we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14/16 patients with available samples at diagnosis, the CLL clonotype was already present in the pre-diagnostic samples. Overall, our data indicate that the pre-clinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases. Overall design: B-cell receptor immunoglobulin heavy chain gene repertoire sequencing of pre-diagnostic and diagnostic samples of CLL patients and matched controls.