Cll Guideline 2005

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    Guidelines on the diagnosis and management of chronic

    lymphocytic leukaemia

    Methods

    The purpose of this guideline is to provide a rational approach

    to the diagnosis and management of patients with chronic

    lymphocytic leukaemia (CLL).

    This guideline has been compiled by the Guidelines

    Working Group of the UK CLL Forum on behalf of the

    British Committee for Standards in Haematology (BCSH).

    Recommendations are based on a review of the literature using

    Medline/Pubmed searches under the heading, CLL, up to

    October 2003 and data presented at the American Society ofHematology in 2003 and at the 10th International Workshop

    on CLL in 2003. The results of meta-analyses and phase 3

    studies that have been published or presented in abstract form

    are included. Treatment recommendations were influenced by

    current and proposed clinical trials in the UK and by guidance

    from The National Institute for Clinical Excellence (NICE). A

    draft guideline was reviewed by members of the UK CLL

    Forum, patient representatives, members of the BCSH and

    a panel of approximately 60 UK haematologists. Their

    comments were incorporated where appropriate. To ensure

    widespread dissemination, the guideline is available on the

    BCSH website.Criteria for levels of evidence and grades of recommenda-

    tion are shown in Table I. The guideline will be reviewed and

    updated in 2005, and a full guideline revision is planned for

    2007.

    Epidemiology

    Chronic lymphocytic leukaemia is the most common type of

    leukaemia in the western world, accounting for 40% of all

    leukaemias in individuals over the age of 65 years. The median

    age of presentation is between 65 and 70 years. CLL is

    extremely rare below the age of 30 years but 2030% of

    patients present under the age of 55 years. The overall

    incidence is approximately 3 per 100 000 per year. Studies

    on the racial and geographic distribution show that CLL is

    2030 times commoner in Europe, Australasia and North

    American white and black populations than in India, China

    and Japan. The male/female ratio in all populations is

    approximately 2:1 (Sgambati et al, 2001).

    There is no good evidence that exposure to chemicals or

    radiation, diet, cigarette smoking, viral infections or auto-

    immune disease are risk factors for the development of CLL.

    However, there is an increase in both lymphoid malignancies,

    including CLL, and a subclinical monoclonal B-cell expansion

    in first and second degree relatives of patients with CLL

    (Houlston et al, 2002; Rawstron et al, 2002). The phenomenon

    of anticipation in which the disease presents earlier and in a

    more severe form in successive generations is seen in manyfamilies with CLL (Yuille et al, 1998).

    The incidence of second malignancies is increased both in

    treated and untreated CLL.

    Diagnosis and prognostic factors

    Diagnostic investigations

    Patients may present with lymphadenopathy, systemic symp-

    toms such as tiredness, night sweats and weight loss or the

    symptoms of anaemia or infection. However, 7080% of

    patients are now diagnosed as an incidental finding on aroutine full blood count. The initial clinical evaluation

    should seek to elicit a family history of lymphoid malig-

    nancy, susceptibility to infection, significant co-morbid

    conditions, and the presence of peripheral lymphadenopathy,

    hepatosplenomegaly and bulky intra-abdominal lymphaden-

    opathy.

    A definitive diagnosis of CLL is based on the combination of

    a lymphocytosis and characteristic lymphocyte morphology

    and immunophenotype.

    Blood count. Current criteria for the diagnosis of CLL

    require a lymphocytosis of >5 109/l. Patients whose

    routine blood count shows a lower level of lymphocytosis

    may subsequently develop clinically significant CLL. Options

    for adult patients with a lymphocytosis of between 3 and

    5 109/l and lymphocyte morphology consistent with CLL

    include immunophenotyping or a follow-up blood count.

    However, there is no evidence that early diagnosis of

    asymptomatic patients with minimal lymphocytosis confers

    clinical benefit.Correspondence: BCSH Secretary, British Society for Haematology,

    100 White Lion Street, London N1 9PF, UK.

    E-mail: janice@b-s-h.org.uk

    guideline

    doi:10.1111/j.1365-2141.2004.04898.x 2004 Blackwell Publishing Ltd, British Journal of Haematology, 125, 294317

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    Lymphocyte morphology. Two subgroups of CLL can be

    distinguished using morphological criteria (Bennett et al,

    1989). In typical CLL >90% of cells are small or medium

    sized lymphocytes with clumped chromatin, indistinct or

    absent nucleoli and scanty cytoplasm. In 15% of patients, the

    morphology is atypical; due to the presence of >10%

    prolymphocytes (CLL/PL) or >15% of cells showing

    lymphoplasmacytoid differentiation and/or cleaved nuclei.

    Immunophenotyping. Immunophenotyping should be performedin all cases requiring treatment and is of particular value in the

    following situations: (i) in cases with low lymphocyte counts to

    confirm the diagnosis of CLL and exclude reactive

    lymphocytosis; and (ii) in patients with atypical lymphocyte

    morphology to exclude other B- or T-cell lymphoproliferative

    disorders. Typically, CLL cells express weak monotypic surface

    immunoglobulin, CD5 CD19, CD23 and weak or absent

    CD79B, CD22 and FMC7. A recommended panel of

    monoclonal antibodies and scoring system for the diagnosis

    of CLL is shown in Table II (Moreau et al, 1997). Using this

    scoring system, 92% of CLL cases score 4 or 5, 6% score 3 and

    2% score 1 or 2. Most other chronic B-cell lymphomas and

    leukaemias score 1 or 2, but a minority score 3.

    Additional investigations

    Additional investigations that may be helpful either at

    presentation and/or during the course of the disease include:

    direct antiglobulin test (DAT) (essential in all anaemic

    patients and before starting treatment);

    reticulocyte count;

    renal and liver biochemistry (including urate levels);

    serum immunoglobulins;

    chest X-ray;

    bone marrow aspirate and trephine biopsy.

    Although marrow examination is not usually essential for the

    diagnosis of CLL, the presence of proliferation centres and

    absence of paratrabecular foci and cyclin D1 nuclear staining

    support a diagnosis of CLL in cases with atypical morphology

    and a low immunophenotype score. Marrow examination is

    also valuable for determining the cause of cytopenias, providing

    prognostic information and assessing the response to therapy.

    Lymph node biopsy. Lymph node histology is not required for

    the diagnosis of typical CLL but may be indicated where the

    diagnosis is uncertain, in patients who develop bulky

    lymphadenopathy (particularly if localized to one lymph

    node area) and to exclude transformation to lymphoma or

    an unrelated cause of lymphadenopathy.

    Cytogenetic/fluorescence in situ hybridization (FISH) analysis. As

    with bone marrow and lymph node biopsy, genetic studies are

    not essential for the diagnosis of typical CLL. However, they

    may be helpful when there is diagnostic uncertainty. It is

    particularly important to exclude a t(11;14) translocation in

    CD5 positive cases with a low immunophenotype score.

    Computed tomography scan and/or ultrasound. These

    investigations may be helpful when the presence of

    splenomegaly is uncertain on physical examination, where

    Table I. Criteria for (A) levels of evidence and (B) grades of recom-

    mendation.

    (A) Levels of evidence

    Level Type of evidence

    Ia Evidence obtained from meta-analysis of randomized

    controlled trialsIb Evidence obtained from at least one randomized controlled

    trial

    IIa Evidence obtained from at least one well designed

    controlled study without randomization

    IIb Evidence obtained from at least one other

    type of well designed quasi-experimental study

    III Evidence obtained from well-designed non-experimental

    descriptive studies, such as comparative studies, correlation

    studies and casecontrol studies

    IV Evidence obtained from expert committee reports or opinions

    and/or clinical experiences of respected authorities

    (B) Grades of recommendation

    Grade Evidence level Recommendation

    A Ia, Ib Required at least one randomized

    controlled trial as part of the body

    of literature of overall good quality

    and consistency addressing specific

    recommendation

    B IIa, IIb, III Required availability of well-conducted

    clinical studies but no randomized clinical

    trials on the topic of recommendation

    C IV Required evidence obtained from expert

    committee reports or opinions and/or

    clinical experiences of respects authorities

    Indicates absence of directly applicable

    clinical studies of good quality

    Table II. Scoring system for the diagnosis of chronic lymphocytic

    leukaemia (CLL).

    Marker

    Score points

    1 0

    Smlg Weak Strong

    CD5 Positive NegativeCD23 Positive Negative

    FMC7 Negative Positive

    CD22 or CD79b Weak Strong

    Scores in CLL are usually >3, in other B-cell malignancies the scores

    are usually

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