Low-Count Monoclonal B-Cell Lymphocytosis Persists after 7 Years of Follow-up and Confers a Higher Risk of Death

Monoclonal B-cell lymphocytosis (MBL) is characterized by the presence of low numbers of circulating clonal B cells that usually display highly-similar phenotypic features to chronic lymphocytic leukemia (CLL) cells. This entity is divided into high-count (MBL^hi) and low-count (MBL^lo), depending on the number of peripheral blood (PB) clonal B cells (higher vs. lower than 0.5x10⁹/L, respectively). Whereas MBL^hi is frequently detected in laboratory routine analyses and precedes CLL, MBL^lo is mainly detected in population-based screening studies, making its biological and clinical significance elusive. Of note, prevalence of MBL^lo is significantly higher than that of MBL^hi and CLL, and increases with age, with a prevalence >20% among individuals older than 70y.

Here, we re-evaluated 65/91 MBL^lo subjects (54 CLL-like and 11 non-CLL-like) followed-up for >5 years (median of 7 years), using high-sensitivity flow cytometry. Cytogenetic alterations related to CLL (i.e. del13q14, trisomy 12, del11(q22-q23) and del17p13) and other chronic B-cell tumors were studied by iFISH in purified MBL clonal B cells.

Overall, the clone size significantly increased (median of 2-3-fold) in 69% of MBL^lo cases, but only one subject progressed to MBL^hi. In parallel, the frequency of cytogenetic alterations increased over time (32% vs. 61% of cases at baseline and at follow-up, respectively). The absolute number of the major T- and NK-cell populations was also increased, but only among CLL-like cases with increased clone size. To prevent a potential age-related bias and to further confirm these findings, we compared the number of PB normal lymphocyte subsets in CLL-like MBL^lo subjects vs . a large series of age- and gender-matched non-MBL healthy donors.

Although progression to CLL was not observed, overall survival of MBL^lo subjects was significantly reduced vs. non-MBL controls studied in parallel (P=0.03) plus the general population from the same region (P≤0.001), particularly among females (P=0.01); infection and cancer, were the main causes of death in MBL^lo. In summary, despite mid-term progression from MBL^lo to MBL^hi and CLL appears to be unlikely, MBL^lo clones persist at increased numbers usually carrying more genetic alterations, in association with higher-risk of death in comparison with healthy individuals, particularly among females.