Monoclonal B-cell lymphocytosis

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. 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 aggressive: Sézary disease 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. 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 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. 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. MBL consist of two groups: low-count MBL has blood B-cell counts <0.5x9 cells/liter (i.e. 0.5x9/L) whereas high-count MBL has blood B-cell counts ≥0.5x9/L but <5x109/L. While low-count MBL does not progress to a malignant disease, high-count MBL does so at a rate of 1-2% per year. MLP-MZ is an exception to this rule in that it s usually associated with B-cell counts >3x109/L and all cases, regardless of B cell counts, have a somewhat higher risk of progressing to a maligant stage. The incidence of all MBL phenotypes increases with age and is strikingly high in the elderly. Below age 40, MBL's incidence is <1% of the general population in most countries but above this age it is found in ~10% of all individuals. The disorder's incidence in individuals >90 may be as high as 75%. Age along with B-cell blood counts, MLB phenotype, and certain genomic abnormalities in the monoclonal B cells are critical considerations in evaluating the clinical implications of MBL and its need for management. MLB falls into three phenotypes that are distinguished based on the cell surface marker proteins which they express viz., the CLL/SLL, atypical CLL/SLL, and non-CLL/SLL phenotypes. These markers are: CD5, CD19, CD20, CD23, and immunoglobulins (Ig) (either Ig light chains or complete Ig, i.e. light chains bound to Ig heavy chains. Distinguishing between these phenotypes is important because they progress to different lymphocyte malignancies. The following table gives the markers for the three MBL phenotypes with (+) indicating the expression (either dim, moderate, or bright depending or the intensity of their expression), (−) indicating the absence of expression, and na indicating not applicable as determined using fluorescent probes that bind the marker proteins. Detection of fluorescent probe binding by the cells requires the use of flow cytometry preferably employing 6 to 8 different fluorescent probes that bind to different markers on 5 million cells from the patient's blood. The table also includes the percentage of MLB cases with the phenotype and the malignancies to which they progress. Cases of non-CLL/SLL MBL in which the monoclonal B cells do not express CD5, CD23, CD10, or CD103 but strongly express CD79B and light chain Ig have been tentatively designated as having monoclonal B-cell lymphocytosis of the marginal zone (i.e. CBL-MZ). This term is used because normal marginal zone B-cell lymphocytes express these markers. Individuals with CBL-MZ commonly present with: B-cell blood counts that are extremely high (>4.0x109; range 3.0x109/L to 37.1x109/L);, represent a large percentage of cases that would otherwise be designated as non-CLL/SLL MLB; often have an IgM monoclonal gammopathy, i.e. high blood levels of a monoclonal IgM antibody; and in addition to the IgM gammopathy, other features that are seen in Waldenström's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance. These individuals are more likely than those with other types of MBL to have their disorder progress to a malignancy. These malignancies appear to have been primarily marginal zone B-cell lymphomas of the splenic marginal zone B-cell, splenic lymphoma/leukemia unclassifiable, hairy cell leukemia, and possibly Waldenström's macroglobulinemia. MBL-MZ requires further studies to evaluate its frequencies, rate of progression to malignancy, and treatment. Most studies on the genomic abnormalities in MBL did not distinguished between the disorder's phenotypes. However, familial studies have found that hereditary factors can contributor to the development of specifically CLL/SLL MLB. Of all the hematologic malignancies, CLL/SLL is the most likely to afflict multiple family members with estimates of familial CLL/SLL ranging from 6 to 10% of all CLL/SLL cases. About 18% of first-degree relatives of individuals with familial CLL/SLL and ~16% of the close relatives of patients with non-hereditary CLL/SLL have CLL/SLL MBL. These associations strongly suggest that inheritable genomic abnormalities contribute to the development of CLL/SLL MLB and, possibly, the progression of this disorder to CLL/SLL. Chromosome abnormalities, single nucleotide polymorphisms (SNPs, i.e. substitutions of a single nucleotide in a DNA sequence at a specific position in the genome) and gene mutations, while each occurs in <15% of cases, are present in CLL/SLL MBL and to some extent are similar to those found in CLL/SLL. For example, position 21.33 to 22.2 on the long (i.e. 'q' ) arm of chromosome 13 is a potential susceptibility locus for familial CLL/SLL. This locus has been identified not only in individuals with familial CLL/SLL but also in their blood relatives who have CLL/SLL MBL. More than 20 SNPs are confirmed risk factors for the development of CLL/SLL; at least 6 of these are also risk factors for CLL/SLL MBL. Finally, the following studies were done on individuals defined as having MBL but din not give its phenotype. Here, these patients are presumed to have the CLL/SLL MBL phenotype. Individuals with low-count and high-count MBL shared with CLL/SLL patients many genomic abnormalities including: deletions of the long arm (i.e. 'q' arm) of chromosomes 11 and 13; deletion of the short arm (i.e. 'p' arm) of chromosome 17; trisomy of chromosome 12; and mutations in NOTCH1, BIRC3, SF3B1, MYD88, ATM, and TP53 genes. In general, the presence and frequency of the mutations in high count MBL were closer than the low count MLB in resembling those in CLL/SLL. All three groups had mutations in the IGH@ region of chromosome 14. This region contains the complex gene that encodes the VDJ region of the heavy chain component of antibodies. Among these mutations, IVGH4-59/61 is most often mutated in low-count MBL while IGHV1-69, IGH2-5, IGHV3-23, IGH23-33, IGHV3-48, and IGHV4-34 are most often mutated in high-count MBL and CLL/SLL. Finally, genetic abnormalities such as the deletion of the q arm in chromosome 13 found in low count MBL are more commonly associated with a favorable prognosis in CLL/SLL while those found in high count MBL, e.g. deletions in the q arm of chromosome 11 or p arm of chromosome 17 are commonly associated with unfavorable prognoses in CLL/SLL. Individuals with MBL-MZ have monoclonal B cell cells that bear complex and distinctive genomic abnormalities, such as deletions and translocations involving chromosome 7, presence of an isochromosome 17, and, rarely, mutations in the NOTCH2 and KLF2 genes. Some of these genomic abnormalities are similar to those found in splenic marginal zone lymphomas and some of the MBL-MZ patients that bore these abnormalities developed this lymphoma. The genetic abnormalities in atypical and non-CLL/SLL MBL have not been well-defined.