CLL-Like MBL In the General Population Persist Over Time, without Clinical Progression, Though Carrying the Same Cytogenetic Abnormalities of CLL

Abstract 2440

Monoclonal B-cell Lymphocytosis (MBL) is a preclinical hematologic condition wherein small B-cell clones are detectable in the peripheral blood of otherwise healthy individuals. Monoclonal B-cell expansions are rather heterogeneous in terms of phenotype, but in two thirds of cases clonal B-cell populations share the same unique immunophenotypic profile of Chronic Lymphocytic Leukemia (“CLL-like MBL”). Based on the number of B cells per μl, MBL cases might be further split into those associated with lymphocytosis, usually diagnosed in a clinical setting (“Clinical MBL”) when clonal B cells reach a concentration >1500/μL, and those detected in the general population (“low-count MBL”), usually characterised by <50 aberrant B cells per μl. It has been proposed that these two entities differ in terms of molecular and clinical features including prognosis. In the case of MBL with lymphocytosis, it has been previously shown and confirmed that they carry a potential risk of progression into clinically overt CLL of about 1.1% per year. On the contrary, very limited data about the outcome of MBL in the general population (“low-count”) exist, though these are the most common forms in otherwise healthy individuals (>20% of people older than 60 years using highly sensitive techniques).

We took advantage of our cohort of 138 MBL cases previously described among 1779 healthy individuals, living in a rural valley in Northern Italy (Val Borbera Valley) that included 96 CLL-like (69.6%), 20 Non-CLL (14.5%), 22 atypical CLL (15.9%) MBL. Of the 138 originally diagnosed MBL subjects, 76 individuals participated to a second visit after a median follow up of 34 months (range 11–50 months). 93.1% (54/58) of CLL-like MBL clones were confirmed, while only 44.5% and 66.7% of Atypical CLL-like and Non-CLL MBL, respectively, persisted over time. The few CLL-like clones that were not confirmed had a very low concentration at the initial visit (median number of clonal B-cells: 0.46 per μl) being proximal to the detection limit of the flow cytometric technique.

Among the confirmed CLL-like cases, 1/54 was a Clinical MBL (1764 cells/μL), 3 subjects had 97, 190 and 265 cells/μl, while the vast majority of participants (50/54, 92.6%), had a number of monoclonal B-cells <50/μl. In comparison with the initial evaluation, during the follow-up analysis, no CLL-like MBL developed a frank leukemia and, in particular, all B-cell expansions with <50 cells per μl remained stable or decreased in terms of absolute count, though some changes occurred in terms of percentage due to a decrease in the normal B cell population as an aging effect. The 3 clones with more than 50 cells per μl at the first evaluation, showed a variable increase in the number of aberrant cells per μL, though all remained below 400 cells/μL; the single clinical MBL case did not show any significant increase.

In order to get further insights in the molecular features of the “low-count MBL”, FACS-sorted aberrant B-cells of 17 cases were subsequently studied by Fluorescence in situ Hybridization (FISH) for the most frequent genomic aberrations detected in CLL patients (del13q, trisomy 12, del11q, del17p). Interestingly, about half of the cases studied (8/17: 47.1%) showed mono- or bi-allelic (in 2 cases) 13q deletions, in a median of 26.7% of MBL cells. One of these cases carried also a 17p deletion that was detected in an additional individual; trisomy 12 and chromosomal deletion of 11q were not identified.

In conclusion, our follow-up study in the general population show that CLL-like MBL tend to persist over time, in clear contrast with Non-CLL and Atypical CLL MBL that appear to be more transient, likely depending on a concomitant inflammatory/infectious status. Interestingly, though we previously reported that low-count CLL-like MBL express an Immunoglobulin repertoire different from clinic MBL and overt CLL, we here show that they do carry 13q deletions in frequency identical to CLL, suggesting the occurrence of this abnormality early during ontogenesis, likely associated with the acquisition of the typical phenotype rather than the progression into an overt leukemic disease. Finally, this follow-up study suggests that the potential risk of progression into clinically frank CLL for population-screening (“low-count”) CLL-like MBL is exceedingly rare if any and definitely less than that of individuals with clinical MBL.