B-Cell Clones as Early Markers for Chronic Lymphocytic Leukemia

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
New England Journal of Medicine (Impact Factor: 55.87). 03/2009; 360(7):659-67. DOI: 10.1056/NEJMoa0806122
Source: PubMed


Otherwise healthy persons with a small number of B-cell clones circulating in the peripheral blood have been designated as having monoclonal B-cell lymphocytosis (MBL). Hospital-based series indicate an excess risk of progression from MBL to chronic lymphocytic leukemia (CLL). In this prospective cohort study, we tested the hypothesis that CLL is always preceded by MBL.
Among 77,469 healthy adults who were enrolled in the nationwide, population-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 45 subjects in whom CLL was subsequently diagnosed (up to 6.4 years later) through the collection of a peripheral-blood sample. Using six-color flow cytometry (with antibodies CD45, CD19, CD5, CD10, kappa, and lambda) and immunoglobulin heavy-chain gene rearrangement by reverse-transcriptase-polymerase-chain-reaction assay, we determined the association between MBL and subsequent CLL and characterized the immunoglobulin gene repertoire of the prediagnostic B-cell clones.
On the basis of either flow-cytometric or molecular analysis, 44 of 45 patients with CLL (98%; 95% confidence interval [CI], 88 to 100) had a prediagnostic B-cell clone; in 41 patients (91%; 95% CI, 79 to 98), the presence of the B-cell clone was confirmed by both methods. The presence of immunoglobulin heavy-chain variable (IGHV) genes was determined in 35 of 45 prediagnostic clones (78%). Of these clones, 16 (46%) were IGHV3 subgroup genes (including 6 [17%] IGHV3-23 genes) and 9 (26%) were IGHV4 subgroup genes (including 4 [11%] IGHV4-34 genes). Furthermore, 27 of 35 of the IGHV sequences (77%) had mutations, with similar distributions after stratification either below or above the median time between the collection of the prediagnostic blood sample and the subsequent CLL diagnosis.
In peripheral blood obtained up to 77 months before a CLL diagnosis, prediagnostic B-cell clones were present in 44 of 45 patients with CLL.

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Available from: Ola Landgren, Jan 04, 2014
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    • "As yet, it is difficult to accurately predict the subset that will progress in MGUS after initial diagnosed and this remains an important area of investigation (3, 8). Interestingly, light-chain MGUS is also a precursor of light-chain MM, which comprises 20% of all MM cases; this association has important implications for understanding the nature of the “feeder” cell for plasma cell malignancy (9–11). Furthermore, progression rates differ, as IgH MGUS transforms at the rate of 1% per year but light-chain MGUS has a progression rate of 0.3% per year, which is significantly lower (4, 6, 12). "
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    ABSTRACT: The plasma cell proliferative disorders monoclonal gammopathy of undetermined significance (MGUS) and malignant multiple myeloma (MM) are characterized by an accumulation of transformed clonal plasma cells in the bone marrow and production of monoclonal immunoglobulin. They typically affect an older population, with median age of diagnosis of approximately 70 years. In both disorders, there is an increased risk of infection due to the immunosuppressive effects of disease and conjointly of therapy in MM, and response to vaccination to counter infection is compromised. The underlying factors in a weakened immune response in MGUS and MM are as yet not fully understood. A confounding factor is the onset of normal aging, which quantitatively and qualitatively hampers humoral immunity to affect response to infection and vaccination. In this review, we examine the status of immune alterations in MGUS and MM and set these against normal aging immune responses. We focus primarily on quantitative and functional aspects of B-cell immunity. Furthermore, we review the current knowledge relating to susceptibility to infectious disease in MGUS and MM, and how efficacy of conventional vaccination is affected by proliferative disease-related and therapy-related factors.
    Frontiers in Immunology 06/2014; 5:257. DOI:10.3389/fimmu.2014.00257
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    • "For example, some patients with monoclonal gammopathy of uncertain significance (MGUS), a condition characterized by the presence of a monoclonal immunoglobulin protein present in the serum, can progress to multiple myeloma [9]. Similarly, a subset of patients with monoclonal B-cell lymphocytosis (MBL), a condition characterized by the presence of a clonal B-cell expansion in the peripheral blood, can progress to chronic lymphocytic leukemia [10]. "
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    ABSTRACT: Subjects with primary Sjogren's Syndrome (SjS) have an increased risk of developing B cell lymphoma and may harbor monoclonal B cell expansions in the peripheral blood. Expanded B cell clones could be pathogenic, and their persistence could exacerbate disease or predispose towards the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B cell clones in the blood of subjects with primary SjS who were treated with rituximab. To determine if circulating B cell clones in subjects with primary SjS emerge or remain following B cell depleting therapy with rituximab, we studied the antibody heavy chain repertoire. We performed single memory B cell and plasmablast sorting and antibody heavy chain sequencing in six rituximab-treated SjS subjects over a one-year follow-up period. Expanded B cell clones were identified in four out of the six rituximab treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH and JH gene segments. We identified one SjS subject with a large expanded B cell clone that was present prior to therapy and persisted following therapy. Somatic mutations in the clone were numerous, but did not increase in frequency over the course of the one-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. For some subjects with primary SjS, these data show that: 1) expanded B cell clones are readily identified in the peripheral blood; 2) some clones are not eliminated by rituximab, and 3) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B cell populations in humans.
    Arthritis research & therapy 02/2014; 16(1):R51. DOI:10.1186/ar4481 · 3.75 Impact Factor
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    • "Thus, the distinction between MBL and Rai stage 0 CLL resides only on the number of absolute neoplastic B-cells. Moreover, Landgren et al. demonstrated that virtually all patients with CLL have a CLL-type MBL phase several years before the CLL diagnosis [5]. Several researchers have tried to compare the outcome of the two forms of lymphoproliferative disorders [3,4,9-13]. "
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    ABSTRACT: Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition defined by the presence of a small (<5 x 10(9)/L) clonal B-cell population in the peripheral blood in the absence of lymph-node enlargement, cytopenias or autoimmune diseases. It is found in approximately 3-12% of normal persons depending on the accuracy of analytical techniques applied. According to the immunophenotypic profile of clonal B-cells, the majority of MBL cases (75%) are classified as chronic lymphocytic leukemia (CLL)-like. This form may progress into CLL at a rate of 1-2% per year. It is thought that CLL is always preceded by MBL. The remaining MBL cases are defined as atypical CLL-like (CD5+/CD20(bright)) and CD5(-) MBL. The MBL clone size is quite heterogenous. Accordingly, two forms of MBL are identified: i) high-count, or 'clinical' MBL, in which an evidence of lymphocytosis (<5 x 10(9)/L clonal B-cells) is seen, and ii) a low-count MBL, in which a normal leukocyte count is found and that is identified only in population-screening studies. Both forms of MBL may carry the cytogenetic abnormalities that are the hallmark of CLL, including 13q-, 17p- and trisomy 12. Consistent with the indolent phenotype of this condition, genetic lesions, such as TP53, ATM, NOTCH1 and SF3B1 mutations, usually associated with high-risk CLL, are rarely seen. Overall, no prognostic indicator of evolution of MBL to overt CLL has been found at present time. However, taking into account this possibility, a clinical and lab monitoring (at least annually), is recommended.
    02/2014; 8:75-79.
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