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Background 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.
Methods 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.
Results 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.
Conclusions 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.
Source Information
From the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (O.L., R.B.H., N.E.C.); and the Center for Biologics Evaluation and Research, Food and Drug Administration (F.A., G.E.M.) — all in Bethesda, MD; Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA (M.A., W.M.); and the Unit and Laboratory of Lymphoid Malignancies, Department of Oncology, Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan (P.G.).
Address reprint requests to Dr. Landgren at the Center for Cancer Research, National Cancer Institute, Bldg. 10, Rm. 13N240, 10 Center Dr., Bethesda, MD 20892, or at landgreo{at}mail.nih.gov.
Related Letters:
The Precursor of Chronic Lymphocytic Leukemia
Mulligan C. S., Best O. G., Mulligan S. P., the Chronic Lymphocytic Leukaemia Australian Research Consortium , Landgren O., Ghia P., Caporaso N. E.
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N Engl J Med 2009;
360:2575-2576, Jun 11, 2009.
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