How Do We Place Monoclonal B-cell Lymphocytosis in the Context of Early, Asymptomatic Chronic Lymphocytic Leukemia?

Twenty years ago, we published in The Hematologist a case report discussing the management of early-stage, asymptomatic chronic lymphocytic leukemia (CLL), addressing the need to develop effective therapeutic strategies at that point in time. In 2014, a colleague sought our opinion on a case of “CLL-like” monoclonal B-cell lymphocytosis (MBL), which can precede the development of CLL. Since MBL is frequently encountered in hematologic practice, a detailed discussion of that condition is warranted.

A 60-year-old male patient, who was free of symptoms, presented with a slightly elevated absolute lymphocyte count (ALC) in the blood on two separate occasions over the preceding six-month period. His past medical history was unremarkable except for the removal of a melanoma in situ from his forehead in 2004. Investigation into the patient’s family history revealed that his 80-year-old mother had CLL, for which she had been receiving therapy for 20 years. In addition, one of his three siblings had a history of recurrent pulmonary infections requiring hospitalization and administration of intravenous antibiotics. In February 2014, the patient’s white blood cell (WBC) count was 8,000, comprising 50% neutrophils and 50% lymphocytes, although his hemoglobin (Hgb) level, hematocrit (Hct), and platelet count were normal. His ALC was 4,000, which is somewhat higher than the upper limit of the normal range. In August 2014, his WBC count was 10,000, comprising 60% neutrophils and 40% lymphocytes, and his Hgb, Hct, and platelet count remained normal. At this time, lymphocyte morphology was totally normal, his ALC remained at 4,000, and neither “B” symptoms nor viral illnesses were observed.

During his first encounter with our team in August 2014, the patient offered no complaints and reported leading an active life, although he expressed concern that he may be harboring CLL like his mother. Further examination revealed no abnormal findings. At this time, complete blood count (CBC) analyses revealed a normal WBC count and an ALC of 4,000, with other elements remaining normal as well. Given the presence of persistent lymphocytosis (>6 months), his blood sample was sent for flow cytometry analysis of peripheral blood mononuclear cells. The analysis indicated that the sample contained 50% CD3⁺ cells and 30% CD19⁺ cells (more than 95% of which co-expressed CD5, CD20, CD23, and an immunoglobulin [Ig] κ light chain), as well as reduced densities of CD20. Based on the over-representation of CD19⁺ B cells bearing CD5, CD23, and low levels of CD20 and monotypic Igκ, the patient was diagnosed with CLL-like monoclonal B-cell lymphocytosis (MBL).

However, since 2014, his WBC and ALC increased at a steady but relatively slow rate. In 2018, when his ALC was 24,000, he was informed that MBL had progressed to CLL, clinical stage 0. In 2023, his ALC was 48,000. His most recent physical examination did not reveal peripheral lymphadenopathy or hepatosplenomegaly. At that time, we repeated flow cytometry, used fluorescence in situ hybridization (FISH) to screen for standard genomic abnormalities, and assessed IGHV mutation status as a prognostic indicator. These analyses revealed a CLL-phenotype (unchanged), del 13q, IGHV mutation consistent with IGHV-mutated CLL, and normal serum immunoglobulin levels. Regular dermatologic examinations did not reveal evidence of melanoma or other skin problems.

Four years after the diagnosis of CLL-like, high-count MBL, we observed conversion to early-stage CLL. The patient has been under follow-up for all 10 intervening years since his referral to our team in 2014, and he continues to maintain an active lifestyle and remains symptom free. Initially, our diagnosis was CLL-type MBL. However, we considered the patient to be at increased risk of developing CLL given his ALC of 4,000, history of melanoma in situ four years earlier (which is not uncommon in people with MBL), his mother’s diagnosis of CLL, and his brother’s history of pneumonia. We reassured him that MBL by itself does not require intervention and recommended follow-up in our clinic at intervals of six to 12 months. The patient agreed with our recommendation for continued follow-up but expressed an interest in learning about clinical trials focused on the treatment of asymptomatic, early-stage CLL.

What are the unique clinical features of “CLL-like” MBL, and how do factors such as clone count, immune features, and infection influence its diagnosis, treatment, and outcomes? How have advancements in hematology over the last 20 years changed our understanding of the disease and these relationships?

Since its introduction in 2005, the definition of MBL as a clinical syndrome has undergone several revisions.¹  Briefly, MBL refers to the persistent elevation of lymphocytes that does not reach the level at which it would be considered CLL (≥5 × 10⁹ B cells/L). Such clones bear a surface membrane phenotype characteristic of CLL cells: CD19⁺CD5⁺CD23⁺CD20^DimIg^Dim. MBL is most often detected by flow cytometry analysis after cells have been exposed to fluorophore-labeled antibodies that react with discrete membrane proteins.

MBL can be divided into two subtypes based on the size of the pre-leukemic clone. A patient is considered to have “high-count MBL” (“clinical MBL”) when the diagnosis is made based on a high number of lymphocytes, which is typically discovered on CBC analysis. In contrast, a patient is considered to have “low-count MBL” when the number of B lymphocytes bearing an MBL surface membrane phenotype in the blood is much smaller, meaning that these cells can only be detected through targeted screening of various populations using immunofluorescence and flow cytometry. The current accepted cutoff between low-count MBL and high-count MBL is 0.5 × 10⁹ B cells/L of blood. Based on this criterion, our patient was diagnosed with high-count/clinical CLL-like MBL.

The prevalence of MBL is approximately 10- to 100-fold higher than that of CLL,²  and its development is influenced by both age and inheritance. In the general population, the prevalence of MBL among those over 40 years of age is remarkably high.²  Depending on the sensitivity of detection, MBL prevalence ranges from approximately 3 to 7% and increases with age into the eighth decade of life, reaching a peak frequency of approximately 15 to 20%. Like CLL, MBL is more prevalent among patients with relatives who have been diagnosed with CLL: The prevalence of MBL in families with two or more members having CLL is approximately 15%. While the incidence of CLL is also clearly influenced by racial/ethnic background, this relationship is less extensively studied for MBL, although Caucasian and Hispanic Americans appear to be at increased risk of developing MBL.³ 

The distinction between low-count and high-count MBL is clinically relevant because their rates of conversion to full-fledged CLL differ significantly. In patients with high-count MBL, the annual rate of conversion to CLL is approximately 3 to 5%. In addition, approximately 1% of patients with MBL require therapy at the time of conversion. In contrast, such transition is not observed in patients with low-count MBL, although low-count MBL clones may increase in number and become high-count MBL.⁴ 

The hypothesis that CLL derives from an MBL precursor state is supported by a series of independent, retrospective analyses of blood samples collected from healthy individuals over time. In summary, samples were subjected to Ig-specific polymerase chain reactions (PCR)^5,6  and deep, next-generation cDNA sequencing,⁷  which revealed that precursors of the leukemic clone were present in almost all people who subsequently developed CLL, in some cases preceding the diagnosis of CLL by a decade or more. Thus, MBL appears to be a prerequisite state preceding CLL.

Since conversion to CLL occurs in a minor subset of individuals, other factors must be involved in the conversion process. Supporting this notion is the finding that most common genetic abnormalities observed using FISH⁸  and other gene defects in patients with CLL are also observed in patients with low- and high-count MBL.^9-11  Notably, at the time of diagnosis, genetic lesions are observed in the cells of 50% of people with high-count MBL, and the expansion of such subclones predicts a shorter time to conversion to CLL requiring treatment.¹² 

The influence of immunologic factors on MBL progression and conversion to CLL differs based on the subtype of MBL. High-count MBL clones bear B-cell receptors (BCRs) that are more like those found in patients with early-stage CLL, whereas low-count MBL clones differ considerably in terms of specific IGHV gene expression and BCR stereotypy.^13,14  Thus, the presence of many low-count MBL clones may not reflect a CLL destiny but rather chronic antigenic stimulation of normal B-cell clones by environmental antigens.¹⁴  The possibility of chronic antigen stimulation is consistent with the limited number of instances in which low-count MBL transitions to high-count MBL and the ultimate lack of conversion to CLL.

Although methods for determining with a reasonable degree of certainty which cases of high-count MBL will transition to CLL requiring therapy are currently unavailable, the numerical size of high-count MBL clones may be the most reliable predictor of conversion from MBL to CLL.15 Additionally, certain prognostic markers imply a greater likelihood of transition from MBL to CLL. Most compelling is the finding that individuals with high-count MBL whose clones are CD38⁺, ZAP-70⁺, or IGHV-unmutated are as likely as those with Rai 0 CLL to require treatment upon conversion to CLL.¹⁶  Moreover, use of the chronic lymphocytic leukemia-international prognostic index (CLL-IPI) appears to anticipate the need for therapy upon conversion of high-count MBL to CLL.¹⁷ 

There is a need to address the association of MBL with other malignancies and significant infections that can require hospitalization. Regarding the former, people with high-count MBL are more likely to develop distinct primary malignancies of the breast, lung, skin, gastrointestinal system, and nervous system than matched, healthy, individuals.¹⁸  A recent retrospective study examining a large cohort of patients with low-count and high-count MBL also revealed a higher incidence of hematologic and lymphoid malignancies in patients, although reduced survival was only observed in people with high-count MBL.¹⁹ 

Regarding significant infections, the likelihood of developing an infection requiring hospitalization is fourfold higher in people with high-count MBL than in matched controls. Notably, the likelihood of developing such an infection is also significantly higher than the likelihood of conversion from MBL to CLL,²⁰  highlighting the importance of infection management in patients with MBL. Moreover, both low- and high-count MBL have been associated with a similar predisposition to developing severe infection.²¹  Indeed, the greater likelihood of developing more severe infection was dramatically evident during the recent COVID-19 pandemic.

Collectively, the increased frequency of other unrelated malignancies and severe infections strongly implies fundamental immune defect(s) in people with low- and high-count MBL. A defect at the B-cell level is manifested by as the frequent development of hypogammaglobulinemia²²  and by the impaired response to immunization frequently observed in people with MBL.^23-26  Although evidence is limited, studies of MBL also suggest differences in the distribution²⁷  and phenotype²⁸  of T-cell subpopulations relative to the normal setting, consistent with a pattern of T-cell dysfunction and immune inhibition.

Thus, a key question that remains to be answered is whether these immune differences and dysfunctions are primary or due to the presence of an overabundance of CLL-like MBL cells that could function as regulatory B cells.

Dr. Rai receives royalties from UpToDate for writing a chapter on CLL. Dr. Chiorazzi indicated no relevant conflicts of interest.