Diagnostic criteria for monoclonal B-cell lymphocytosis Gerald E. Marti, 1 Andy C. Rawstron, 2 Paolo Ghia, 3 Peter Hillmen, 2 Richard S. Houlston, 4 Neil Kay, 5 The ´re `se A. Schleinitz 1,6 and Neil Caporaso 7 on behalf of The International Familial CLL Consortium* 1 Center for Biologics Evaluation and Research (CBER), US Food and Drug Administration (FDA), NIH, Bethesda, MD, USA, 2 Haematological Malignancy Diagnostic Service, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK, 3 Department of Oncological Sciences, University of Torino and Laboratory of Cancer Immunology, Istituto per la Ricerca e la Cura del Cancro, Candiolo (TO), Italy, 4 Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK, 5 Division of Hematology, Mayo Clinic, Rochester, MN, USA, 6 Institut Paoli-Calmettes, Marseille Cedex9, France, and 7 Department of Medicine, Division of Cancer Epidemiology and Genetics, Genetic Epidemiology Branch, National Cancer Institute, NIH, Bethesda, MD, USA Summary Very low levels of circulating monoclonal B-cell subpopula- tions can now be detected in apparently healthy individuals using flow cytometry. We propose the term ‘monoclonal B-cell lymphocytosis’ (MBL) to describe this finding. The aim of this document is to provide a working definition of MBL for future clinical, epidemiological and laboratory studies. We propose that the detection of a monoclonal B-cell population by light chain restriction is sufficient to define this condition in individuals not meeting the diagnostic criteria for other B-lymphoproliferative disorders. The majority of individuals with MBL will have cells that are indistinguishable from chronic lymphocytic leukaemia (CLL). However, this blood cell clonal expansion of CD5 + or CD5 ) B-lymphocytes is age- dependent and immunophenotypic heterogeneity is common. Longitudinal studies are required to determine whether MBL is a precursor state to CLL or other B-lymphoproliferative disease in a situation analogous to a monoclonal gammop- athy of undetermined significance and myeloma. Future studies of MBL should be directed towards determining its relationship to clinical disease, particularly in individuals from families with a genetic predisposition to developing CLL. Keywords: monoclonal B-cell lymphocytosis, B cells, early detection, surrogate biomarker, familial chronic lymphocytic leukaemia. The increasing technological ability to detect monoclonal B cells using three- and four-colour flow cytometry has led to the identification of very low levels (<0Æ005 · 10 9 cells/l) of circulating clones of B cells with surface features similar to chronic lymphocytic leukaemia (CLL) in apparently healthy individuals. Such clones are now being detected within the context of an absolute lymphocyte count of 5Æ0 · 10 9 /l or below the level required for a diagnosis of CLL. If these clonal expansions are implicated in the aetiology of CLL then their study has the potential to offer insight into the molecular development of CLL in general. A variety of terms have entered the literature to designate this finding. Followed by a meeting of the International Workshop on CLL at the National Cancer Institute (NCI) in Bethesda, MD, a subcom- mittee of the International Familial CLL consortium was formed to summarize the literature and to propose a unified nomenclature to describe the finding of a monoclonal expansion in healthy individuals. Here, we define monoclonal B-cell lymphocytosis (MBL) as the flow cytometric detection of a light chain restricted lymphocytosis. In addition to providing a working definition of MBL we suggest areas for further study. History and population prevalence of MBL Chronic lymphocytic leukaemia is defined by the presence of monoclonal B-lymphocytes co-expressing CD19, CD5 and CD23, with weak or no expression of CD20, CD79b, FMC7 and surface immunoglobulin. The monoclonal B cells must represent the majority of leucocytes with an absolute lympho- cyte count >5 · 10 9 cells/l, which has persisted for at least 1 month (Cheson et al, 1996). Several investigators have demonstrated that patients fitting within these criteria had disease that was stable for long periods of time, and have used a variety of different names to denote this situation. It has also Correspondence: Gerald E. Marti, MD, PhD, CMDR (PHS), Flow and Image Cytometry Section, LSCB DCGT OCTGT, CBER FDA NIH Bdg 29B Rm 2NN08, 8800 Rockville Pike, Bethesda, MD 20892, USA. E-mail: gemarti@helix.nih.gov Received 6 January 2005; accepted for publication 18 March 2005 *Other contributing members of the IFCLL: Pablo Bertin, Federico Caligaris-Cappio, Timothy Call, Daniel Catovsky, Finbarr Cotter, James Cerhan, Nicholas Chiorazzi, Guillaume Dighiero, Robin Foa, Lynn Goldin, Viggo Joensson, Michael Keating, Thomas Kipps, Francessca R. Mauro, Kanti Rai, Laura Rassenti, Sara Strom, Robert Vogt and Peter Wiernik. review ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130, 325–332 doi:10.1111/j.1365-2141.2005.05550.x