Monoclonal B-cell lymphocytosis (MBL) in CLL families: substantial increase in relative risk for young adults

Family studies demonstrate that there is an inherited component in a significant proportion of CLL patients. The average age of onset in familial CLL is approximately 10–20 years earlier than in sporadic CLL, suggesting that familial anticipation occurs although this may be due to ascertainment bias.1, 2 We have previously reported the development of a sensitive flow cytometric assay which can detect as little as a single CLL cell in 105 leucocytes without prior knowledge of any immunophenotype or genotype.3 This assay is therefore applicable to identifying extremely low levels of clonal CLL cells in apparently normal individuals. It is possible to detect a monoclonal B-cell lymphocytosis with CLL-phenotype (MBL-CLL) in 3.5% of healthy individuals over 40 years old (32/910).4 In 59 healthy first-degree relatives of patients from 21 CLL families, MBL-CLL was detected in 8/59 relatives (13.5%), representing a highly significant increase in prevalence (age-adjusted logistic regression analysis, P=0.00002).5 These data have now been confirmed in independent studies.6, 7

Two of the eight individuals were under 40 years old, and to directly compare these relatives with appropriate controls we have screened a further 365 normal individuals aged 16–40 years. MBL-CLL was detectable in only 0.3% (1/365) of the otherwise normal young adults. The age distribution of MBL-CLL in normal individuals therefore mimics that of clinical CLL; in contrast the proportion of affected individuals in familial CLL is high at all ages. The overall relative risk for detection of MBL-CLL in families is fourfold in comparison to the general population but for young adults the relative risk rises to 17-fold (Table 1). The detection of MBL-CLL is independent of ascertainment bias and provides strong confirmatory evidence of inherited genetic susceptibility to CLL in some families. The fact that familial CLL shares a similar range and frequency of the major prognostic factors8 indicates that there is a pre-disposition to all types of CLL. The data suggests that, at least in a proportion of families, there is an inherited abnormality that increases susceptibility to development of CLL at a much earlier age than the general population, thus increasing the life-long risk of developing a clinically apparent CLL clone within the family as a whole.

Table 1 Relative risk of detection of CLL-phenotype monoclonal B-cell lymphocytosis in the general population and in normal relatives from CLL families


  1. 1

    Yuille MR, Houlston RS, Catovsky D . Anticipation in familial chronic lymphocytic leukaemia. Leukemia 1998; 12: 1696–1698.

  2. 2

    Goldin LR, Pfeiffer RM, Li X, Hemminki K . Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish family-cancer database. Blood 2004; 104: 1850–1854.

  3. 3

    Rawstron AC, Kennedy B, Evans PA, Davies FE, Richards SJ, Haynes AP et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98: 29–35.

  4. 4

    Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA et al. Monoclonal B lymphocytes with the characteristics of ‘indolent’ chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 2002; 100: 635–639.

  5. 5

    Rawstron AC, Yuille MR, Fuller J, Cullen M, Kennedy B, Richards SJ et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood 2002; 100: 2289–2290.

  6. 6

    Ghia P, Prato G, Scielzo C, Stella S, Geuna M, Guida G et al. Monoclonal CD5+ and CD5− B-lymphocyte expansions are frequent in the peripheral blood of the elderly. Blood 2004; 103: 2337–2342.

  7. 7

    Marti GE, Carter P, Abbasi F, Washington GC, Jain N, Zenger VE et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom 2003; 52: 1–12.

  8. 8

    Sakai A, Marti GE, Caporaso N, Pittaluga S, Touchman JW, Fend F et al. Analysis of expressed immunoglobulin heavy chain genes in familial B-CLL. Blood 2000; 95: 1413–1419.

Download references


Supported by the Leukaemia Research Fund and Yorkshire Cancer Research.

Author information

Correspondence to A C Rawstron.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

de Tute, R., Yuille, M., Catovsky, D. et al. Monoclonal B-cell lymphocytosis (MBL) in CLL families: substantial increase in relative risk for young adults. Leukemia 20, 728–729 (2006).

Download citation

Further reading