Prevalence Of Monoclonal B-cell Lymphocytosis Research Articles

Abstract 5256: Incidence of squamous cell carcinoma (SCC) in a large screening cohort of monoclonal B-cell lymphocytosis (MBL)

Abstract MBL is a common pre-malignant condition characterized by circulating clonal B-cells with an absolute B-cell count <5x109/L and no lymphadenopathy, organomegaly, or cytopenias. MBL is the precursor to CLL. The incidence of cutaneous SCC in CLL is significantly higher compared to controls. The incidence of SCC in MBLs has not yet been determined. Study participants from the Mayo Clinic Biobank who had no prior history of hematologic malignancy, were 40 years or older, and were Olmsted County residents completed a health questionnaire and provided blood samples between 7/2009 and 12/2020. Stored peripheral blood mononuclear cells were screened for MBL using flow cytometry. We defined three MBL immunophenotypes: CLL-like MBL (CD5+, CD20dim), atypical MBL (CD5+, CD20+), and non-CLL-like MBL (CD5-, CD20+). MBL individuals were also classified by cell count into low-count MBL (LC-MBL) and high-count MBL (HC-MBL), with HC-MBL having a percent clonal B-cell count ≥85%. Data on newly diagnosed SCC was abstracted from the medical records, and prior history of skin cancer before sample collection was ascertained from patient questionnaires. Individuals were followed from sample date to the earliest of SCC, death, loss to follow-up, progression, or 12/31/2020. Cumulative SCC incidence was adjusted for competing risk of death. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age and sex. A total of 5,470 participants were screened for MBL and included 949 (17%) with LC-MBL, 63 (1%) with HC-MBL, and 4,458 (81%) controls (negative for MBL). Individuals with HC-MBL (median age 75 years) or LC-MBL (median age 73 years) were significantly older (P<0.001) than controls (median age 66 years). There were 41 (65%) males among HC-MBL, 447 (47%) among LC-MBL, and 1,551 (35%) among controls. Prior skin cancer history was highest among HC-MBLs (N=17, 27%) or LC-MBLs (N=236, 25%) compared to controls (N=767, 17%). After a median follow-up of 18 months (range 0-138), 154 of the 5,470 individuals were identified to have incident SCC following MBL screening. At least one SCC was observed in 3 individuals with HC-MBL, 33 individuals with LC-MBL, and 118 controls. The 5- and 10-year cumulative incidence of SCC in individuals with MBLs was 7% and 16%, respectively; control estimates were 4% and 8%, respectively. However, after adjusting for age and sex, we observed no evidence of an association between MBL and risk of incident SCC (HR=0.95, CI=0.65-1.40, P=0.80), nor when we stratified individuals by age or by sex (all P>0.05). In the largest MBL screening cohort to date, individuals with MBL do not have an increased risk of incident SCC compared to controls. In contrast to individuals with CLL, these individuals with screening MBL do not need increased dermatologic examination for skin cancer, which is important given the high prevalence of MBL (18% of the population above age 40). Citation Format: Ahmed Nadeem Ansari, Sara J. Achenbach, Sameer A. Parikh, Geffen Kleinstern, Aaron D. Norman, Kari G. Rabe, Connie E. Lesnick, Timothy G. Call, Janet E. Olson, James R. Cerhan, Neil E. Kay, Celine M. Vachon, Esteban Braggio, Curtis A. Hanson, Tait D. Shanafelt, Christian L. Baum, Susan L. Slager. Incidence of squamous cell carcinoma (SCC) in a large screening cohort of monoclonal B-cell lymphocytosis (MBL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5256.

Prevalence and Overall Survival of Low Count Monoclonal B-Cell Lymphocytosis (LC-MBL): A Screening Study of 8,297 Individuals from the Mayo Clinic Biobank

Prevalence and Overall Survival of Low Count Monoclonal B-Cell Lymphocytosis (LC-MBL): A Screening Study of 8,297 Individuals from the Mayo Clinic Biobank

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

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.

Prevalence and Immunophenotypic Characteristics of Monoclonal B-Cell Lymphocytosis in Healthy Korean Individuals With Lymphocytosis.

Epidemiological studies of monoclonal B-cell lymphocytosis (MBL) have been conducted in limited geographical regions. Little is known about the prevalence of MBL in Asia. We investigated the prevalence and immunophenotypic characteristics of MBL in Koreans who had idiopathic lymphocytosis (lymphocyte count >4.0×109/L) and were ≥40 years of age. A total of 105 leftover peripheral blood samples met these criteria among those from 73,727 healthy individuals who visited the Health Promotion Center, Samsung Medical Center, Korea, from June 2018 to August 2019. The samples were analyzed using eight-color flow cytometry with the following monoclonal antibodies: CD45, CD5, CD10, CD19, CD20, CD23, and kappa and lambda light chains. The overall prevalence of MBL in the study population was 2.9% (3/105); there was one case of chronic lymphocytic leukemia (CLL)-like MBL (CD5+CD23+), one case of atypical CLL-like MBL (CD5+CD23−), and one case of CD5−MBL with a lambda restriction pattern. This is the first study on the MBL prevalence in an East Asian population, and it reveals a relatively low prevalence of MBL in healthy Korean individuals with lymphocytosis.

Monoclonal B-cell lymphocytosis in blood donors in Turkey

ABSTRACTObjectives: Monoclonal B-cell lymphocytosis (MBL) is a precursor state of chronic lymphocytic leukemia (CLL) with peripheral lymphocytosis below 5 × 109/l. The diagnostic criteria exclude the presence of lymphadenopathy, organomegaly, infections, autoimmune diseases or any sign of a lymphoproliferative disorder. This prospective study was designed in order to evaluate the frequency of MBL in blood donors in Turkey.Methods: The diagnosis of MBL was identified by flow cytometry method based on the International Familial CLL Consortium Report. A total of 999 volunteers [median age 34 (18–78) years; male/female: 705/294] were included in the study.Results: Monoclonal B-cell lymphocytosis was demonstrated in 18 cases (1.8%). A total of 16 cases (1.6%) was evaluated as CLL-like MBL, while 2 (0.2%) had a non-CLL-like phenotype. The subjects were divided into three groups according to age, as <40 years, 40–60 years and >60 years. The prevalence of MBL was 1.1% below 40 years, 0.6% between 40 and 60 years and 0.1% in cases over 60 years, without statistical significance (p > 0.05).Discussion: The sensitivity of the flow cytometry method is essential and may be responsible for the variations in the prevalence of MBL in different populations which can also be attributed to study design, higher detection rates in the elderly and families with genetic predisposition to CLL.Conclusion: Large population-based studies and standardized laboratory methods are needed to determine the potential risk factors of progression to CLL, including molecular markers and genetic profile.

Risk of Cancer in Patients with Clinical Monoclonal B-Cell Lymphocytosis (MBL): A Cohort Study of Newly Diagnosed Patients Compared to Controls.

AbstractAbstract 2893 Introduction:Monoclonal B-Cell Lymphocytosis (MBL) is a common asymptomatic condition characterized by a clonal B-cell population detected in the blood or bone marrow. The prevalence of MBL is approximately 3–5% in adults over age 40 but rises with age. MBL is a precursor state to CLL and other types of indolent non-Hodgkin lymphoma (NHL). Only a small subset of patients with MBL comes to clinical attention, typically during evaluation for low grade lymphocytosis (designated now as clinical MBL). The rate of progression to CLL requiring treatment among individuals with clinical MBL is ∼1%/yr, and the vast majority of patients with MBL will never develop a B-cell malignancy. Recent data indicate that individuals with MBL are at increased risk of infection similar to CLL. It is unknown whether individuals with MBL are at risk for other adverse outcomes associated with CLL, such as increased risk of non-hematologic cancers (NHC). We investigated the incidence of NHC among patients with clinical MBL and compared this to a cohort of general medicine patients and a cohort of CLL patients. Methods:Mayo Clinic Rochester (MCR) is the primary center for hematologic care in a region including southeastern Minnesota, northern Iowa, and western Wisconsin. No other hematology specialty centers are available within a 50 mile radius of MCR. To explore the risk of NHC in a local, community dwelling cohort of individuals with clinically-identified, CLL-phenotype MBL, we used the MCR CLL database to identify all individuals with newly diagnosed MBL seen in the MCR Hematology Division between January 1, 1999 and December 31, 2009. Analysis was limited to 154 MBL cases residing within 50 miles of MCR. The comparison cohort consisted of 596 adult general medicine patients, with no prior cancer, residing within 50 miles of MCR, who were seen for a general medical exam and enrolled as controls in a case-control study for NHL between April 25, 2004 and December 31, 2009. Rates of NHC in the MBL cohort were also compared to a cohort of 174 patients with newly diagnosed CLL seen in the same time interval as the MBL cohort and also living within 50 miles of MCR. NHC were identified using the Mayo Clinic Cancer Tumor Registry as well as review of medical records in all 3 cohorts. Patients with a NHC diagnosis >3 months prior to the diagnosis date of MBL/CLL were excluded from analysis while those with MBL/CLL and a NHC within 3 months of one another were considered to have a concurrent diagnosis. Results:There were 125 patients in the MBL cohort, 153 in the CLL cohort, and 596 in the control cohort after excluding patients with prior cancers. The MBL and CLL patients tended to be older (median age MBL=69, CLL=68, Control=58; p<0.0001) and more likely to be male (% male MBL=61, CLL=67, Control=46; p<0.0001) than the controls.After a median follow-up of 4.2 years (range 0–11), 20 (16%) individuals with MBL developed NHC as compared to 22 (4%) of the controls (Hazard Ratio (HR) MBL relative to control=5.0; 95% confidence interval (CI)=(2.6, 9.4; p<0.0001). Twenty CLL patients (13%) developed NHC, supporting a similar rate to that of MBL patients (HR MBL relative to CLL=1.3; 95% CI=(0.6, 2.5; p=0.49;See Figure). Specifically, the MBL cohort had a higher incidence of cancer of the breast, lung, and nervous system than that of the control cohort. The higher risk of NHC among individuals with CLL and MBL persisted even when patients with “concurrent diagnosis” of CLL/MBL and NHC were excluded (p=0.006) and when patients treated for progressive CLL were censored at the date of treatment (p=0.001)Finally, we performed a pooled multivariable analysis of all patients (n=874) adjusting for age, sex, major co-morbidities, presence of MBL, and diagnosis of CLL. Age (HR each year older=1.03; 95% CI 1.01–1.06; p=0.003), major comorbidities (HR=1.81; 95% CI 1.07–3.00; p=0.02), CLL (HR=2.10; 95% CI 1.01–4.01; p=0.04), and MBL (2.47; 95% CI 1.30–4.69; p=0.02) were independent risk factors for NHC. The results were similar when the effects of age was modeled in a non-linear (e.g. logarithmic) manner. Conclusions:In this cohort study, patients with newly diagnosed clinical MBL had a 2.5-fold increased risk of developing NHC relative to the control cohort. MBL was an independent risk factor for development of NHC after adjusting for age, sex, and other comorbidities. This finding adds to the growing evidence that clinical MBL has a distinct clinical phenotype. [Display omitted] Disclosures:Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

Case study interpretation-Portland: Case 1

Case study interpretation-Portland: Case 1

Clinical Aspects of Monoclonal B-Cell Lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic precursor condition for chronic lymphocytic leukemia (CLL). It is defined by the presence of small clones of aberrant B cells in the peripheral blood, with a total B-cell count below the threshold for diagnosis of CLL (<5.0x10(9) cells/L). The authors review current literature on the prevalence of MBL, and the clinical course of this CLL precursor condition, and recommended management for individuals with MBL. MBL occurs in approximately 4% to 5% of healthy adults. While most cases of CLL are preceded by MBL, progression to leukemia requiring CLL treatment occurs in only 1% to 2% of individuals with MBL per year. The absolute B-cell count is most strongly associated with progression, and patients with low-count MBL identified in population screening studies rarely develop CLL. Studies are ongoing to better define the relationship between MBL and CLL and to identify prognostic indicators that predict which patients will progress to CLL. Given their elevated risk of developing malignancy, individuals with clinical MBL should be monitored at least annually for progressive lymphocytosis and signs or symptoms of CLL. Many of the epidemiologic and genetic factors associated with MBL development and its progression to CLL have not yet been identified. However, ongoing studies by many research groups are aimed at answering these questions to facilitate management of individuals with this premalignant condition. In addition, active investigation of MBL will likely yield new insights into the biology of CLL, potentially identifying new therapeutic targets for this incurable disease.

Prevalence of MBL Increases Over Time In Relatives of CLL Families,

Abstract 3881 Background:Chronic lymphocytic leukemia (CLL) is largely incurable neoplasm of the blood and has one of the highest familial risks of disease among cancers. Monoclonal B-cell lymphocytosis (MBL) with a CLL immunophenotypic profile (i.e., CLL-like MBL) is a precursor state to CLL. In the general adult population, the prevalence rate of MBL is 5–9% and increases with age. This is in contrast to the 13–18% rate of MBL in first-degree relatives of CLL patients from high-risk families (defined here as families with at least two confirmed living cases of CLL). Few longitudinal studies of MBL incidence exists. One study evaluated MBL status over time in a cohort of individuals with MBL from a rural valley in Northern Italy. Our work herein will be the first to evaluate the status of MBL over time in relatives of CLL patients from high-risk families. Methods:Using a cohort of 41 high-risk CLL families, we evaluated the MBL status and clonal blood B-cell counts in 94 relatives of CLL patients at two time points at least 1 year a part. High sensitivity, multi-color flow cytometry was performed on fresh or previously frozen blood samples in three laboratories: Duke University, the US Food and Drug Administration, and Mayo Clinic. The number of cell events collected for flow cytometry evaluation varied from 1 to 5 x105 cells. To assure concordance across flow cytometry laboratories, 15 samples were evaluated at multiple labs. The concordance of MBL calling was a 100%. We defined three monotypic B-cell subsets as CLL-like MBL (CD5+ CD20dim), atypical MBL (CD5+ CD20+), and non-CLL like MBL (CD5−CD20+). Results:Of the 94 relatives, the median age at consent was 57 years (range 42–93) and 39% were male. At the initial MBL screening, 70 (74%) relatives had normal immunophenotype (NIPT) and 24 (26%) had MBL (1 atypical MBL, 3 non-CLL like MBL, and 20 CLL-like MBL). Seven of the 24 individuals with MBL had monoclonal B-cell counts available at baseline screening; median = 147.4 cells/uL (range 22.7–1663). The 94 relatives underwent repeat evaluation with a median follow up time of 1.8 years (range 1–6). At the second evaluation, we found an increase in the prevalence of MBL, with 11 of the 70 (12%) initially NIPT relatives developing a new MBL clone (10 CLL-like, 1 non-CLL like). These 11 incident MBL cases were from 9 families with 2 families each having 2 relatives changing MBL status. The median number of monoclonal B-cells in these 11 incident MBL cases was 0.58 cells/uL (range 0.38–60.3). The 23 out of the 24 relatives with baseline MBL (20 CLL-like MBL and 3 non-CLL like MBL) had a persistent MBL clone. Only 6 of these 23 individuals had monoclonal B-cell counts available at both time points, and among these 6, the clonal B-cell counts decreased at follow-up screening; median difference −64.1 cells/uL (range −1204.3– 10.5). The second evaluation of the initial atypical MBL relative had too few clonal cells for flow assessment. Conclusion:We found that our CLL-like MBL clones persisted over the period of observation in relatives from high-risk CLL families; this finding is similar to that previously reported using a population-based study conducted in Northern Italy. Notably, 12% of relatives from high-risk CLL families developed incident MBL during just 2 years of follow up. Although these MBL clones are all low count (< 1500 cells/uL), these data provide further evidence that MBL is a marker of inherited predisposition to CLL. It will be important to see how our rate of change of MBL status compares to that of the general population as we continue to follow our cohort of CLL families. Disclosures:No relevant conflicts of interest to declare.

Monoclonal B-Cell Lymphocytosis (MBL) in Blood Donors: Age- and Sex-Specific Prevalence, Clone Size, and IGHV-IGHD-IGHJ Rearrangements

Abstract 2840Recent studies using sensitive flow cytometry methods have reported up to 14% MBL prevalence among older adults. Although MBL has been detected in donated blood, a systematic study of MBL prevalence in blood donors is lacking. We initiated the first such study, using high sensitivity immunophenotyping and ensuring exclusion of repeat donors. Here we report results from the first ten months.Starting in May 2010, samples from 1090 blood donors over 44 years old were collected at a regional U.S. blood center. Samples were immunophenotyped by flow cytometry with a six-color antibody cocktail (CD19, CD20, CD5, CD45 and κ/λ immunoglobulin light chains). At least 500, 000 events were collected on a FACS Canto II flow cytometer. Histograms were examined for phenotypic patterns consistent with B cell clonality. Samples were classified as MBL when at least 50 clonal B cells were detected. MBL immunophenotypes were categorized into typical chronic lymphocytic leukemia (CLL)-like, atypical CLL-like, or non-CLL-like (CD5 negative). Samples from MBL cases underwent PCR amplification, and IGHV- IGHD- IGHJ gene rearrangements were sequenced when possible.The overall MBL prevalence (Table 1) was 7.7% (84/1090). The sex-specific prevalence was 4.2% in women and 10.2% in men. The prevalence increased with increasing age for men. In women the prevalence increased sharply from the 45–54 age group to the 55–64 age group. The prevalence in the >64 age group of women appeared to drop, but this estimate is unreliable due to the small number of observations. Multivariate log-binomial regression modeling showed that male sex and increasing age are independent risk factors for MBL: the age-adjusted prevalence ratio for sex (men/women) was 2.3 (95%CI 1.4–3.7; p=0.001), while the sex-adjusted prevalence ratio for age group 65 and older compared to the youngest age group (45–54) was 2.1 (95%CI 1.2–3.7; p=0.006). [Display omitted] The median absolute B-cell count was comparable in blood donors with and without MBL (167/μl vs. 160/μl). The clonal B-cell count in donors with MBL was low (median 11/μl, 10th-90th percentiles 1–122). However, the clonal count was much higher (median 333/μl, 10th-90th percentiles 90–2887) in the subset of MBL donors in whom more than 80% of the B-cells were clonal. Moreover, the clonal B-cell counts in atypical CLL-like and non-CLL-like MBL were higher (median 37/μl, n=31) than in typical CLL-like MBL (median 4/μl, n=53) (p=0.0002).Of the 84 MBL cases, 82 were PCR-amplified and examined for monoclonal bands reflecting IGHV-IGHD-IGHJ rearrangement. In the 29 samples where monoclonal banding was detected, the median clonal count was 40/μl, while it was only 8/μl in 53 samples where no monoclonal banding was detected. Of the 29 samples with monoclonal banding, 19 were heavily mutated (<97% germline), 6 minimally mutated (97–99%), and 4 unmutated (100%); 21 (72%) were IGHV3, and the remaining 8 (28%) were IGHV4 (Figure 1). CLL-related IGHV genes were uncommon. [Display omitted] This study has so far revealed a much higher prevalence of MBL in donated blood than previously reported. The majority of MBL in this population are mutated, CLL-like, low count MBL, which has also been seen in residential population studies. These findings suggest that MBL in donated blood typically represents indolent MBL rather than clinical MBL. However, the biology of MBL is still being elucidated. Given the reported association (Castillo et al, Blood 2010) between red blood cell transfusions and non-Hodgkin lymphoma (particularly the aggregate category CLL/SLL), our findings underscore the need to ascertain long-term outcomes in recipients of blood from MBL donors. In addition, these results will be important in interpreting findings from other studies of MBL prevalence and risk factors. Disclosures:No relevant conflicts of interest to declare.

3.15 Prevalence of MBL Increases over Time in Relatives of CLL Families

Abstract Abstract 3881 Background: Chronic lymphocytic leukemia (CLL) is largely incurable neoplasm of the blood and has one of the highest familial risks of disease among cancers. Monoclonal B-cell lymphocytosis (MBL) with a CLL immunophenotypic profile (i.e., CLL-like MBL) is a precursor state to CLL. In the general adult population, the prevalence rate of MBL is 5–9% and increases with age. This is in contrast to the 13–18% rate of MBL in first-degree relatives of CLL patients from high-risk families (defined here as families with at least two confirmed living cases of CLL). Few longitudinal studies of MBL incidence exists. One study evaluated MBL status over time in a cohort of individuals with MBL from a rural valley in Northern Italy. Our work herein will be the first to evaluate the status of MBL over time in relatives of CLL patients from high-risk families. Methods: Using a cohort of 41 high-risk CLL families, we evaluated the MBL status and clonal blood B-cell counts in 94 relatives of CLL patients at two time points at least 1 year a part. High sensitivity, multi-color flow cytometry was performed on fresh or previously frozen blood samples in three laboratories: Duke University, the US Food and Drug Administration, and Mayo Clinic. The number of cell events collected for flow cytometry evaluation varied from 1 to 5 x105 cells. To assure concordance across flow cytometry laboratories, 15 samples were evaluated at multiple labs. The concordance of MBL calling was a 100%. We defined three monotypic B-cell subsets as CLL-like MBL (CD5+ CD20dim), atypical MBL (CD5+ CD20+), and non-CLL like MBL (CD5−CD20+). Results: Of the 94 relatives, the median age at consent was 57 years (range 42–93) and 39% were male. At the initial MBL screening, 70 (74%) relatives had normal immunophenotype (NIPT) and 24 (26%) had MBL (1 atypical MBL, 3 non-CLL like MBL, and 20 CLL-like MBL). Seven of the 24 individuals with MBL had monoclonal B-cell counts available at baseline screening; median = 147.4 cells/uL (range 22.7–1663). The 94 relatives underwent repeat evaluation with a median follow up time of 1.8 years (range 1–6). At the second evaluation, we found an increase in the prevalence of MBL, with 11 of the 70 (12%) initially NIPT relatives developing a new MBL clone (10 CLL-like, 1 non-CLL like). These 11 incident MBL cases were from 9 families with 2 families each having 2 relatives changing MBL status. The median number of monoclonal B-cells in these 11 incident MBL cases was 0.58 cells/uL (range 0.38–60.3). The 23 out of the 24 relatives with baseline MBL (20 CLL-like MBL and 3 non-CLL like MBL) had a persistent MBL clone. Only 6 of these 23 individuals had monoclonal B-cell counts available at both time points, and among these 6, the clonal B-cell counts decreased at follow-up screening; median difference −64.1 cells/uL (range −1204.3– 10.5). The second evaluation of the initial atypical MBL relative had too few clonal cells for flow assessment. Conclusion: We found that our CLL-like MBL clones persisted over the period of observation in relatives from high-risk CLL families; this finding is similar to that previously reported using a population-based study conducted in Northern Italy. Notably, 12% of relatives from high-risk CLL families developed incident MBL during just 2 years of follow up. Although these MBL clones are all low count ( Disclosures: No relevant conflicts of interest to declare.

Monoclonal B-cell lymphocytosis: a brief review for general clinicians.

Monoclonal B-cell lymphocytosis (MBL) is a recently described medical condition that displays biological similarities to the most common subtype of adult leukemia in the Western world, i.e. chronic lymphocytic leukemia (CLL). Diagnostic criteria have been published with the aim of differentiating between these two entities. The overall prevalence of MBL is at least 100 times higher than that of CLL, which indirectly suggests that MBL is not necessarily a pre-leukemic condition, although in some circumstances, CLL cases can really be preceded by MBL. In view of this high prevalence rate, general clinicians and even non-hematological specialists have a high chance of being faced with individuals with MBL in their routine clinical practice. MBL is classified as "clinical MBL", "population-screening MBL" and "atypical MBL" and the clinical management of affected individuals depends greatly on this differentiation. The present review provides a guide to diagnosing and following up MBL patients.

Immunologic aspects of monoclonal B-cell lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic condition wherein small numbers of clonal B cells can be detected in the blood of otherwise healthy individuals. Most MBL have a surface immunophenotype nearly identical to that of chronic lymphocytic leukemia (CLL), though other phenotypes can also be identified. MBL has been shown to be a precursor state for CLL, but most MBL clones are quite small and apparently have minimal potential to progress of CLL or other B-cell lymphoproliferative disorder (B-LPD). The investigation of MBL as a precursor state for CLL will likely lead to important insights into mechanisms of disease pathogenesis. The review will cover clinical and translational aspects of MBL, with a particular emphasis on the prevalence of MBL; the relationship between MBL, CLL, and other B-LPDs; and the capacity of MBL to modulate the normal B- and T-cell compartments.

CD5-Negative Monoclonal B-Cell Lymphocytosis (MBL) Is Detectable In 9% of Adults Aged Over 40 but Phenotypes Associated with Clinically Common Non-Hodgkin Lymphomas Are Infrequent (

AbstractAbstract 2002 Introduction:Monoclonal B-cells with a Chronic Lymphocytic Leukemia (CLL) phenotype are detectable in more than 10% of adults in the general population using high sensitivity flow cytometry assays designed to detect minimal residual disease after treatment. However, the prevalence of MBL with a phenotype corresponding to other B-lymphoproliferative disorders (B-LPD) is less than 2% of the general population even using the most sensitive assays. No studies have reported CD10+ MBL whereas several studies have demonstrated that the t(14;18) is frequently detectable in the general population at a level which should be detectable by flow cytometry. The lack of CD10+ MBL may indicate that the t(14;18) alone rarely results in the expansion of a clonal B-cell population in the blood, or that currently available assays are inadequate for detecting circulating follicular lymphoma. We have previously investigated 66 markers to determine the best candidates for diagnosis and monitoring B-LPD, which were then tested in over 1500 cases. We have developed a single-tube assay to screen for residual disease that can detect lymphoma cells when they represent as few as 1 in 10,000 leucocytes. The aim of this study was to asses the frequency with which lymphoma-phenotype monoclonal B-cells are detected in the general population using a high sensitivity assay. Methods:Cells from 679 individuals (342 male, 337 female, median age 64, range 40–99) with a normal blood count and no current or prior history of cancer were incubated with antibodies to Kappa, Lambda, CD19, CD20, CD5, CD10, LAIR1, CXCR5 and 0.5 million cells were acquired using a BD FACSCanto II cytometer. In cases with detectable MBL further phenotyping was performed and B-cells were selected and stored for FISH and molecular clonality studies. Results:MBL was detected 129/679 cases (19.0%): CLL-type MBL in 86/679 cases (12.7%), non-CLL MBL in 60/679 cases (8.8%) with both CLL-type and non-CLL MBL were present in 17/679 cases (2.5%). Within the non-CLL MBL group, in 21/60 cases the monoclonal B cells had no additional features to confirm a neoplastic population and it was not possible to ascertain whether these were neoplastic cells or a reactive population with a highly skewed kappa/lambda ratio. Of the remaining 39 specimens: none showed evidence of germinal centre differentiation; 12 (1.7% of total) showed a phenotype most consistent with marginal zone lymphoma/lymphoplasmacytic lymphoma; and 27 cases expressed strong levels of LAIR1 coupled with strong CD19 and CD20 and an extended phenotype that is relatively rare in clinical B-LPD, restricted to hairy cell leukemia and a small proportion (<15%) of marginal zone lymphomas. Conclusions:Using an assay designed for detection of residual disease in lymphoma it was possible to detect non-CLL phenotype MBL in 8.8% of individuals over 60 years of age with normal blood counts and no history of cancer. Only a small number of these cases had a phenotype comparable to follicular lymphoma or marginal zone lymphoma, which constitute the majority of clinically significant indolent B-LPD. The complete absence of cases with a germinal centre phenotype contrasts with the high frequency of detection of BCL2-IGH rearrangement by PCR in the peripheral blood of healthy individuals. The flow cytometry assay used in this study readily detects circulating cells with appropriate phenotype in patients known to have follicular lymphoma, diffuse large B-cell lymphoma or marginal zone lymphoma/lymphoplasmacytic lymphoma and the data indicate a high specificity for peripheral blood based diagnosis and monitoring in these conditions. The most clinically prevalent lymphomas are rarely detectable in peripheral blood in individuals without lymphadenopathy but there is a surprisingly frequent development in the general population of both CLL and a restricted subset of marginal zone lymphomas which may indicate a common developmental pathway. Disclosures:No relevant conflicts of interest to declare.

Prevalence of monoclonal B‐cell lymphocytosis: A systematic review

Individuals with monoclonal B-cell lymphocytosis (MBL) have been identified in clinic outpatients, in unaffected relatives of patients with chronic lymphocytic leukemia (CLL), and in general populations. MBL and its relationship with CLL have been actively investigated over the last decade. This report systematically reviews the prevalence of MBL in the context of the populations studied and the evolution of laboratory methods used to define MBL. To identify published studies that have assessed the prevalence of MBL, we systematically searched the MEDLINE databases and consulted with members of the International MBL Study Group. We reviewed the 10 articles that were identified by this process. We abstracted information on study populations, laboratory tests, criteria for designating MBL, and the reported frequencies. Three of the ten studies were published in 2009, three between 2007 and 2008, and four between 2002 and 2004. Reported prevalences varied widely, ranging from 0.12 to 18.2%. This variability was clearly associated with both the laboratory methods and the populations studied. MBL was more common among older individuals and kindred of persons with CLL. The most common MBL subtype was CLL-like MBL. Large population-based studies of MBL that employ standardized laboratory methods with a consensus case definition are needed to assess prevalence and establish risk factors. These studies should include prospective follow-up of MBL cases to determine the relationship between MBL and CLL. Data from original studies should be reported in sufficient detail to allow future synthesis of information from multiple studies, such as meta-analysis.

A computer simulation for exploring the detection of monoclonal B‐cell lymphocytosis by flow cytometry

Monoclonal B-cell lymphocytosis (MBL) is defined by the presence of monoclonal B-cells in peripheral blood in the absence of hematologic disease. MBL is detected by flow cytometry with increasing frequency as the number of B-cells acquired increases. Computer simulations in R language were used to examine the impact of increasing the number of B-cells acquired on the sensitivity of detecting MBL and to explore the possibility of detecting distinct B-cell clones among polyclonal B-cell populations. With simulated populations containing 0.1%-1.0% monoclonal B-cells, the number of clonal B-cells detected showed a normal distribution in the upper range of clonal cells acquired and more nearly log-normal as the distributions became bounded by 0. The distributions peaked around the clonal prevalence. The detection of MBL increased sharply with a small increase in the total number of B-cells acquired when the number of clonal cells acquired was near the MBL cutoff point. MBL could be detected in log-normally distributed polyclonal B-cell populations. Sampling variability in detecting monoclonal B-cells can be investigated through simulation. The observed population prevalence of MBL can be approximated with reasonable assumptions about the distribution of clonotypes in the circulating B-cell compartment.

Monoclonal B cell lymphocytosis: Clinical and population perspectives

Monoclonal B Cell Lymphocytosis (MBL) refers to clones of CLL-like cells that exhibit CLL characteristics that fall short of the numbers required for CLL diagnosis. Data from large CLL kindreds document increased prevalence of MBL suggesting a genetic contribution to its etiology. The molecular features that favor progression of MBL to CLL are poorly understood but an elevated B-cell count is a risk factor for progression. An important consideration when evaluating volunteers from CLL families who are willing to donate bone marrow is that MBL be ruled out since the MBL donor clone could result in a second CLL in the recipient. Further studies of MBL are needed to identify the molecular features and how they evolve during progression.

Monoclonal B‐cell lymphocytosis in first‐degree relatives of patients with sporadic (non‐familial) chronic lymphocytic leukaemia

Although biological similarities have been described among monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukaemia (CLL), the relationships between these two conditions are not fully understood, and new epidemiological studies in different populations and different countries continue to be reported. Here, we investigated 167 first-degree relatives from 42 families of patients with non-familial (sporadic) CLL, using four-colour flow cytometry. MBL was found in seven of 167 subjects (4.1%). Monoclonality was detected in all cases either by light-chain restriction or by polymerase chain reaction. Fluorescence in situ hybridization did not show any chromosomal abnormality. The prevalence of MBL according to age was 0 (0/54) in individuals aged less than 40 years, 2.5% (2/81) between 40 and 60 years, and 15.6% (5/32) in individuals over 60 years. The prevalence of MBL cases in individuals over 60 years was similar to that found in familial CLL relatives at the same age group. This suggests that in older first-degree relatives of patients with sporadic CLL, the risk of MBL detection is as high as in older first-degree relatives from CLL families, which could render these individuals belonging to 'sporadic CLL families' as susceptible as individuals from 'familial CLL' to the development of clinical CLL.

Overview of monoclonal B‐cell lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) has been the subject of more intensive investigation for the last 10 years. The increased presence of MBL in unaffected, first-degree relatives with familial chronic lymphocytic leukaemia (CLL) suggest that it is surrogate marker for early disease. In normal population studies, MBL is found to be increased in ageing subjects. Consensus criteria for the diagnosis of MBL have been proposed. The differential diagnosis has been further clarified and the prevalence of MBL is most prominent in the elderly. The aetiology of MBL is unknown but probably involves immune mechanism of senescence or altered response. Environmental health studies suggest that exposure to certain toxins may lead to MBL but further work is needed. MBL is a precursor to CLL but may also regress, remain stable or progress to clinical CLL.

Monoclonal B‐cell lymphocytosis in blood donors

Monoclonal B-cell populations have been detected in the peripheral blood of apparently healthy individuals by flow cytometry. In 2005, the term monoclonal B-cell lymphocytosis (MBL) was proposed to describe these findings. MBL may be immunophenotypically similar to chronic lymphocytic leukaemia (CLL) and, like CLL, the prevalence is higher in males and older individuals. We studied the prevalence of MBL in blood donors from the Midwestern United States. Samples from 5141 donors were examined and seven (0.14%) were found to have immunophenotypic characteristics of MBL or CLL. Immunoglobulin heavy chain analysis yielded monoclonality or oligoclonality. Prior and subsequent to the study, an additional undetermined number of blood donors were screened and seven of these expressed immunophenotypic characteristics of MBL or CLL. We thus found a total of 14 healthy blood donors with monoclonal expansions of B-lymphocyte populations. Of these, 12 were presumptively classified as MBL and two as CLL. All but two of the donors were male; the mean age was 59 years. The clinical importance of these findings with regard to transfusion medicine has not been established.