Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families

Abstract

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Graphical abstract

Figure 1.

Cumulative incidence and 95% CI of progression to CLL. (A) Among 449 relatives, including both those without MBL and with MBL. (B) Among the 139 with known low-count MBL.

Figure 2.

Change of percent clonal B cells of total B cells by age among the 131 relatives who had at least 1 CLL-like MBL clone documented at follow-up and have not yet progressed to CLL. Note the different y-axis scale values among figures. Dark circles represent CLL-like MBL. Open circles represent no MBL or other MBL. (A) All 131 individuals. (B) Individuals (n = 72) whose maximum percent B-cell levels were <10%. (C) Individuals (n = 40) whose maximum percent B-cell clone levels were 10% to 84%. (D) Individuals (n = 19) whose maximum percent B-cell clone levels were ≥85%.