Monoclonal B-Lymphocytosis: Analysis of the Incidence, Demographics, Nature and Subclassification in 414 Patients

Abstract

The 2008 Guidelines for Chronic Lymphocytic Leukemia require a B-cell count ≥5.0×109/L (Hallek et al, Blood , 111, 5446, 2008). Clonal B-cell populations below <5.0×109/L, and in the absence of adenopathy, organomegaly or cytopenia, are defined as Monoclonal B-Lymphocytosis (MBL) (Marti et al., Br. J. Haematol., 2005). We analysed the frequency and nature of small B-cell clonal populations identified in a large, non-hospital based pathology laboratory servicing both metropolitan and regional areas of New South Wales, Australia. There were 414 patients identified from 2000 to 2005 with an incidental finding of a B-cell clone with total B-lymphocytes (defined as CD19+ cells) <5.0×109/L fulfilling the criteria for MBL. There were 212 males (51%) and 202 females (49%) with a mean age of 69.7 years (range 14–97 years). Patients could be clearly divided into two major groups: 322 (77.7%) with a typical chronic lymphocytic leukaemia (CLL) phenotype (MBL[cll]) and 92 (22.3%) with a ‘non-CLL’ phenotype (MBL[nhl]). Analysis of MBL[cll] showed a near equal gender distribution of 168 (52.2%) males and 154 (47.8%) females with a mean age of 70.6 years (range 41–94 years). No patient had a CLL clone aged younger than 40 years, and for each subsequent age decade there were 4% (40–49 yrs), 13% (50–59yrs), 23% (60–69yrs), 40% (70–79yrs), 18% (80–89yrs) and 2% (>90yrs) of the patients with a CLL clone, mirroring the age distribution of CLL. The mean clonal level (CD19/CD5+) was 2.36×109/L (range 0.01–5.21×109/L), the mean B-cell count (CD19+) 2.50×109/L (range 0.02–4.97 ×109/L) and the mean absolute lymphocyte count (ALC) was 4.71 ×109/L (range 0.4–10.5×109/L. Over half (52%) of these patients fulfilled NCI-1988/1996 criteria for the diagnosis of CLL (with ALC ≥5.0×109/L). The ALC was within the laboratory reference range (1.0–4.0 ×109/L) in only 22% of patients. Follow-up analysis on a representative cohort of 146 patients showed progression to a lymphocyte count >30×109/L in 15 patients over a mean of 4.03 (range 1–8) years, and including 3 patients with clonal populations originally measuring <1.5×109/L. Analysis of the 92 patients with a ‘non-CLL’ phenotype (MBL[nhl]) showed 44 (47.8%) males and 48 (52.2%) females, with a mean age of 66.7 years (range 14–97 years). The mean clonal level in this group was 1.27×109/L. The level of the clonal population with MBL[nhl] was <2.0×109/L in 77% and <3.0×109/L in 92% of patients. There were 66 patients (71.7%) with MBL[nhl] with a phenotype of “lymphoma not otherwise unspecified” (i.e. pan-B cell+, monoclonal surface immunoglobulin++, CD5−, CD10−, CD103−) and the remainder had ‘specific’ diagnosis possible on review of the peripheral blood morphology and phenotype as follows: 'Mantle Cell Lymphoma'-like (CD5+, CD23+) - 10 (10.9%), Splenic Lymphoma with Villous Lymphocytes - 7 (7.6%), 'Follicular Lymphoma' (CD10+) - 4 (4.3%), Hairy Cell Leukaemia (CD103+) - 4 (4.3%), Hairy Cell Leukemia Variant - 1 (1%). MBL is not uncommon in the immunophenotyping laboratory and can be conveniently divided into two dominant groups, the majority with a phenotype typical of CLL (MBL[cll]), while there are a range of non-CLL phenotype identified (MBL[nhl]), some with a ‘specific’ diagnosis. In 322 patients with an MBL[cll] clone below the defined cut-off point for CLL of B-cells <5.0×109/L, the absolute B-cell count is a linear continuous variable. This data suggests that MBL[cll] is not a precursor state or predisposition but rather the same biological process as early CLL (separated by an arbitrary definitional cut-off) from which some will progress but many will remain stable.