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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    • "However, ImmunoSEQ NGS could not replace SCA for verifying clonal identity. In all CLL cases, clonal cells are present prior to the diagnosis of CLL, with multiclonality in low-count MBL293031. In the majority of cases, only a single transformed clone reaches the threshold for massive clonal expansion. "
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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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