Monoclonal B Lymphocytosis – Diagnosis, Treatment

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Monoclonal B Lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 109/L B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL). MBL can be categorized as either low count or high count based on whether the B-cell count is above or below 0.5 × 109/L. Low-count MBL can be detected in ∼5% of adults over the age of 40 years when assessed using standard-sensitivity flow cytometry assays. A number of biological and genetic characteristics distinguish low-count from high-count MBL. Whereas low-count MBL rarely progresses to CLL, high-count MBL progresses to CLL requiring therapy at a rate of 1% to 2% per year. High-count MBL is distinguished from Rai 0 CLL based on whether the B-cell count is above or below 5 × 109/L. Although individuals with both high-count MBL and CLL Rai stage 0 are at increased risk of infections and second cancers, the risk of progression requiring treatment and the potential to shorten life expectancy are greater for CLL.

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic condition in which individuals have increased blood levels of particular subtypes of monoclonal lymphocytes (i.e. an aberrant and potentially malignant group of lymphocytes produced by a single ancestral cell). This increase must persist for at least 3 months.[rx] The lymphocyte subtypes are B-cells that share certain features with the abnormal clones of lymphocytes that circulate in chronic lymphocytic leukemia/small lymphocyte lymphoma (CLL/SLL) or, less frequently, other types of B-cell malignancies. Some individuals with these circulating B-cells develop CLL/SLL or the lymphoma types indicated by their circulating monoclonal B-cells. Hence, MBL is a premalignant disorder[rx]

Types of Monoclonal B Lymphocytosis

In 2005, the International Familial CLL Consortium proposed the term “monoclonal B lymphocytosis” to define the presence of CLL-phenotype cells in the peripheral blood in the absence of other features of CLL or SLL. The initially proposed diagnostic criteria for CLL phenotype MBL are as follows:

  • Documentation of a clonal B-cell population in peripheral blood (light-chain restriction [abnormal κ/λ ratio or low sIg in >25% B cells] or heavy-chain monoclonal IGHV rearrangement).
  • B-cell count <5 × 109/L.
  • Presence of CLL phenotype (CD5, CD19, CD23 positive; CD20 and sIg dim [reduced]).
  • No evidence of lymphoma, infection, or autoimmune conditions.

This entity was later acknowledged by the International Working Group of CLL, which in 2008 revised the 1996 National Cancer Institute-sponsored Working Group diagnostic criteria for CLL and SLL to include MBL. These revisions also redefined the threshold to diagnose CLL based on the absolute B-lymphocyte count rather than the ALC.

In 2017, the World Health Organization (WHO) reclassified MBL as a distinct entity in which individuals have: 

  • 1) an excessive number of circulating monoclonal B-cells;
  • 2) lack evidence of lymphadenopathy, organomegaly, or other tissue involvements caused by the these cells;
  • 3) no features of any other B cell lymphoproliferative disease such as one of the B-cell lymphomas; and
  • 4) evidence that these cells have either a CLL/SLL, atypical CLL/SLL, or non-CLL/SLL phenotype based on these cells’ expression of certain marker proteins.[rx][rx] A fourth MBL phenotype, monoclonal B-cell lymphocytosis-marginal zone (i.e. MBL-MZ) appears to be emerging as a distinct form of non-CLL/SLL MBL.[rx]

Diagnosis of Monoclonal B Lymphocytosis

Diagnostic Criteria and Sub-classification for MBL(adapted from ())

 1. Documentation of clonal B-cell population1 by one or more of following:
  a. light chain restriction:

  • overall kappa:lamda ratio >3:1 or <0.3:1 or

  • greater than 25% of B-cells lacking or expressing low level surface Immunoglobulin

  b. heavy chain monoclonal IGHV rearrangements
 2. Presence of a disease specific immunophenotype2
 3. Absolute B-cell Count <5 x 109 cells/L
 4. No other features of a lymphoproliferative disorder or autoimmune disease
  a. normal physical exam (no lymphadenopathy or organomegaly)
  b. absence of B-symptoms (e.g. fatigue, weight loss, night sweats) attributable to NHL
  c. no autoimmune/infectious disease
A. CLL Like phenotype
 - co-expression of CD5 with CD19; CD20 (dim); and CD23
 - light chain restriction with dim surface immunoglobulin expression (very small MBL clones may be oligoclonal and thus not light chain restricted)
B. Atypical CLL phenotype
 - co-expression of CD5 with CD19 but CD23 negative or CD20 (bright)
 - light chain restriction with moderate to bright surface immunoglobulin expression
 - exclude t(11;14) to rule out mantle cell lymphoma
C. Non-CLL phenotype
 - CD5 negative
 - Express CD20
 - light chain restriction with moderate to bright surface immunoglobulin expression
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Blood B-cell counts

Individuals with MBL usually present with unexplained increases in blood lymphocyte counts (i.e. lymphocytosis). The most common causes for lymphocytosis are viral infections, autoimmune diseases (particularly connective tissue diseases), hypersensitivity reactions, acute stress reactions, and prior splenectomy.[rx] Unlike many individuals with lymphocytosis due to the latter disorders, individuals with MBL are asymptomatic, may have a family history of CLL/SLL, are usually >40 years old, and may have a history of serious infections (high-count MBL is ~3-fold more likely than age-matched healthy controls to have a history of serious infections and infection-related hospitalizations[rx]).[rx] The diagnosis of MBL in these patients depends on finding 0.5-5×109 monoclonal B cells that express the makers characteristic of CLL/SLL MLB, atypical CLL/SLL MLB, non-CLL/SLL MLB, or MLB-MZ.[rx] However, individuals with CBL-MZ commonly present with B-cell blood counts that are extremely high (>4.0×109; range 3.0×109/L to 37.1×109/L);[rx] and may have an IgM monoclonal gammopathy.[rx]

Bone marrow involvement

Most individuals with MBL have at presentation an abnormal infiltrate of monoclonal B-cells in their bone marrow as determined by biopsy. These B cells represent a median value of ~20% of all nucleated cells in the marrow. Regardless of the percentage of these cells, the presence of monoclonal B cells in bone marrow does not appear to influence the malignant progression of MBL[rx] and is not part of the criteria used to diagnose the disorder.[rx]

Nodal MBL

MBL patients may present with asymptomatic lymphadenopathy (i.e. lymph nodes that are enlarged or abnormal in consistency). In one study, ~42% of MBL patients had enlarged lymph nodes as detected by CT scans. Nonetheless, these patients’ rate of progression to malignant disease does not differ from that for MBL patients that had normal CT scans. However, patients who have grossly enlarged (i.e. >1.5 centimeters) (cm) lymph nodes on physical examination do have a greater risk of progression. It has been recommended that patients with ≥1 lymph node larger than 1.5 cm be diagnosed as having Cll/SLL, that patients with lymph nodes ≤1.5 cm in size be diagnoses as having normal MBL, and that CT scans should not be used in diagnosing or staging MBL.[rx]

MBL with autoimmune cytopenia

Rare patients with MBL may present with the autoimmune disease-induced cytopenias of hemolytic anemia (reduced circulating red blood cell numbers) or thrombocytopenic purpura (reduced circulating platelet numbers).[rx] In the past, cases of CLL/SLL MBL associated with an autoimmune disease were diagnosed as CLL/SLL. However, patients with these autoimmune disorders who have very small B cell clones either never develop a lymphocyte malignancy or, rarely, do so and only after many years. Coinsequently, it is now widely recognized that such cases, when associated with very small numbers of monoclonal B-cells, are best diagnosed as CLL/SLL MBL with autoimmune cytopenia rather than CLL/SLL.[rx]

Tissue-based MBL

Monoclonal CLL/SLL phenotype B cells have been found using sensitive flow cytometry methods in various tissues.[rx] They have been identified as infiltrates in 1.9% of liver biopsies and 0.4% of prostate tissues obtained at prostatectomy. While the significance of these lesions is unknown, the presence of extensive infiltrations that replace normal tissue is more consistent with a diagnose of CLL/SLL than CLL/SLL MBL.[rx]

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Differential diagnosis

The key factor that distinguishes low-count CLL/SLL-MLB, high-count CLL/SLL-MLB, and CLL/SLL is the number of circulating monoclonal B cells, as described above. However, the other MLB phenotypes may progress to and/or be mimicked by various monoclonal B-cell lymphocyte malignancies. The key cell markers and other points that help distinguish the following MBL phenotypes from these malignancies include the following (refer to Table for comparisons to non-malignant predecessor cells):

Atypical CLL/SLL-MBL

  • Mantle cell lymphoma: The monoclonal B-cells in this aggressive lymphoma are CD5+ in most cases, CD10−, CD23−, CD43+, CD103−, complete Ig+, and express cyclin D1; these cells have translocations between chromosomes 11 and 14 in >95% of cases and in many cases overexpress the SOX11 transcription factor gene.[rx] Testing for chromosome 11, 14 translocations has been recommended for all cases of atypical and non-CLL/SLL MBL.[rx]
  • Follicular lymphoma: The monoclonal B-cells in this indolent lymphoma are CD5−, CD10+/−, CD19+, CD20+, CD23+/−, CD103−, CD200−, and complete Ig+. These cells often exhibit translocations between chromosomes 14 and 18.[rx]


  • Splenic marginal zone lymphoma: The monoclonal B-cells in this indolent lymphoma are CD5+/−, CD10−, CD19+, CD23−, CD43−, CD103−, and do not express cyclin D1. These cells may bear deletion in the “q” arm of chromosome 7 (30% of cases), and mutations in NOTCH2 (10-25% of cases), KLF2 (10-40% of cases), and, rarely, MYD88 genes.[rx] The monoclonal cells are also CD200− and are complete Ig+.[rx] Patients with this lymphoma commonly have an enlarged spleen.[rx]
  • Splenic B-cell lymphoma/leukemia unclassifiable: The rare reports on this lymphoma find the monoclonal B cells to be CD19+, CD20+ (bright, CD23+, CD11+, CD25−, CD103−, CD72+, and annexin A1−.[rx] These cells, similar to the monoclonal cells in Hairy cell leukemia,[rx] may have the V600E mutation in the BRAF gene. Patients with this lymphoma commonly have enlarged spleens.[rx]


  • Splenic marginal zone lymphoma and splenic B-cell lymphoma/leukemia: see above descriptions.
  • Waldenström’s macroglobulinemia: The monoclonal B-cells in this indolent lymphoma are CD5− (in most cases), CD10−, CD19+, CD23−, CD43−/+, CD103−, cyclin D1+,[rx] Cd200−, and globulin + (dim).[rx] The cells contain the L265P mutation in the MYD88 (>90% of cases) and a mutation in the CXCR4 gene (30% of cases).[rx] Patients with this lymphoma commonly have an IgM gammopathy, i.e. high blood levels of an IgM monoclonal protein.[rx]
  • Hairy cell leukemia: The monoclonal B-cells in this usually indolent CLL/SLL-like leukemia have distinctive morphology and are CD5−, CD10−, CD19+, CD20+ (bright), CD23−, CD103+, CD200+, and complete Ig+.[rx]

In situ lymphoid neoplasia

In situ lymphoid neoplasia (ISLN), a lymphocyte disorder newly categorized by the World Health Organization (2016,) has several features in common with MLB. Like MBL, it is an asymptomatic, premalignant disorder of B-cells that is associated with the circulation of these cells and may progress to follicular lymphoma, mantle cell lymphoma, or CLL/SLL. ISLN differs from MBL in that its neoplastic B-cells accumulate in the follicles of lymphoid tissue, usually circulate in very low numbers, and bear distinctive genetic abnormalities that differ from those in MBL. ISNL is diagnosed based on, and requiring, the finding of these neoplastic B-cells in lymphoid follicles.[rx]

Treatment of Monoclonal B Lymphocytosis

Low-count MBL is an indolent disorder that in virtually all individuals does not progress to a malignant phase. Overall survival in low count MBL does not differ from that found in age-matched healthy individuals.[rx] MBL-MZ is an exception to this rule: this disorder generally presents with high monoclonal B-cell counts and regardless of the level of these counts may progress to a malignant phase at a greater than that found in other forms of MBL.[rx]

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Depending on its phenotype (see above Table), high-count MBL progresses to CLL/SLL, mantel cell lymphoma, follicular lymphoma, splenic marginal zone lymphoma, or splenic lymphoma/leukemia unclassifiable at a rate of 1-2% per year[rx] whereas MBL-MZ progresses to a marginal zone B-cell lymphoma, Waldenström’s macroglobulinemia, or Hairy cell leukemia at a ~3% per year.[rx] Factors predisposing to this progression in CLL/SLL MBL include the expression of CD38 cell-surface glycoprotein on the monoclonal B-cells, deletion of the short arm of chromosome 17 in these cells,[rx] high serum levels of beta-2 macroglobulin,[rx] and circulating B cell levels >10×109/L.[rx] There is relatively little information on the features promoting the progression of atypical CLL/SLL MBL, non-CLL/SLL MBL, and MBL-MZ to their respective lymphomas.

Individuals with high-count MBL (studies based primarily on the CLL/SLL phenotype) are at an increased risk for developing:

  • 1) cancers of the breast, lung, and gastrointestinal tract in up to 13% of all cases;
  • 2) autoimmune hemolytic anemia and immune thrombocytopenic purpura;
  • 3) unexplained kidney disease as manifested by chronic kidney disease and/or the nephrotic syndrome; and
  • 4) serious infections.[rx] While earlier studies suggested that only very high-count MBL (i.e. >10×109 B-cells/L) was associated with a decrease in survival,[rx] more recent studies indicate that high-count MBL (i.e. (i.e. >0.5×109 B-cells/L) do show a shorter overall survival.[rx] In addition to having very high numbers of B-cells, high-count CLL/SLL MLB patients whose monoclonal B cell clone lacks mutations in IGVH genes (see above section on genome abnormalities) or whose |β2 macroglobulin is elevated have a shortened survival. However, the shortened survival times in high-count CLL/SLL MBL does not appear due to its progression to CLL/SLL. Rather, this shortened survival appears due to the disorders’ susceptibility to serious infections, other types of cancers, immune cytopenias, and renal disease.[rx]

Recommended treatments for patients with high-count MBL[rx] and MBL-MZ[rx] include yearly follow-up evaluations to test for the malignant progression of their disorder and for the development of other forms of cancer, infections, immune cytopenias, and renal disease. It may also be beneficial to ensure that high-count MLB patients are up to date on vaccinations including those for influenza, pneumococcal pneumonia, and tetanus before they become more severely immunocompromised by the progression of their disorder. In all cases live vaccines should be avoided in these individuals.[rx]

Key Areas for Future MBL Research

I. Identification of epidemiologic factors associated with development of MBL

  • genetics

  • health behaviors

  • exposures

II. Clinical outcome of low count MBL

  • CLL like MBL

  • atypical and non-CLL phenotype MBL

  • prognostic markers

III. Identification of clinical and biologic parameters that allow optimal classification of patients with small B-cell clones (MBL vs. CLL vs. SLL)

  • characteristics of the clone

  • characteristics of the host/environment

IV. Identification of the biologic events related to progression of MBL to CLL or other NHL

  • biologic events in the clonal B-cells

  • biologic events/interactions related to the host/environment

  • genetic characteristics of the clone

  • germline genetic characteristics of the host

  • behaviors

  • exposures

V. Studies exploring a potential tissue equivalent of MBL



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