CLL-like monoclonal B-cell lymphocytosis: are we all bound to have it?

CLL-like monoclonal B-cell lymphocytosis (MBL) shares a unique immunophenotype with chronic lymphocytic leukemia (CLL), and represents the vast majority of clonal B-cell expansions found in the peripheral blood of otherwise healthy subjects. Along with the improvement of laboratory techniques and the widespread availability of multiparameter flow cytometry, the finding of tiny aberrant B-cell populations became more frequent, prompting the need for clinical and biological definition of the nature of this condition and its relationship with leukemia development. MBL seems to be a melting-pot containing several entities, identical in terms of phenotype but with extremely different risks of leukemia development (from low to none) that seem to correlate with the number of B lymphocytes. CLL-like MBL observed in the clinical setting ("Clinical MBL"), usually being characterized by lymphocytosis, demonstrated a sizeable, even if low (1.1-1.4% per year), risk of leukemic progression, but represents a minority of all MBL cases. The vast majority of CLL-like MBL are detected in general population screenings and do not likely have a risk of CLL that is substantially higher than that of unaffected individuals. Interestingly, MBL frequency increases with age, being virtually undetectable under 40 years of age but being present in 50-75% of the people older than 90 years. It has been proposed that MBL could be interpreted as an epiphenomenon of a chronic and persistent antigenic stimulation. The (rare) possibility to evolve into a frank leukemia might then depend on biological and molecular factors insofar unknown that may modify the modality of cell reaction as well as the potential to acquire further genetic abnormalities. Therefore, the real challenge of the next years in the MBL research field is not to increase the sensitivity of detection, neither to implement screening protocols to be applied to the general population, rather to unravel the biologic features that, at individual level, will identify those (few) cases that are at risk of developing a progressive disease.