Chronic lymphocytic leukemia (CLL) is a malignant, chronic lymphoproliferative disorder characterized by proliferation and accumulation of monoclonal B-cells in the bone marrow, peripheral blood, lymph nodes, liver and spleen.

It is the most common form of adult leukemia in the Western world but rare in Asians.

Exact etiology is unknown but usually associated with genetic aberrations and lesions.


Chronic%20lymphocytic%20leukemia Diagnosis


  • Diagnosis is based on the following criteria:
    • Presence of monoclonal B-cell lymphocytes ≥5 x 109/L in peripheral blood
    • Clonality of circulating B lymphocytes confirmed by flow cytometry
    • Chronic lymphocytic leukemia cells are small, mature-looking lymphocytes with a narrow border of cytoplasm, dense nucleus with no visible nucleoli, and with partially aggregated chromatin
    • Immunophenotype: CD5, CD19, and CD23; low CD20, CD79b and FMC7 (typically negative); CD10 and cyclin D1 negative
  • Assess patient's performance status based on clinical presentation


Classification of Chronic Lymphocytic Leukemia (CLL)

  • Two staging systems are being used to predict patient outcome
  • Also used in assessing patients to be included in clinical trials

CLL Staging Systems

Rai System

  • A staging system based on physical examination and complete blood count results used to assess the degree of tumor burden
  • Stage Description Risk Status1
    0 Lymphocytosis >5 x 109/L and >40% lymphocytes in bone marrow Low
    I Stage 0 with enlarged node(s) Intermediate
    II Stage 0-I with splenomegaly, hepatomegaly, or both Intermediate
    III Stage 0-II with Hgb <11.0 g/dL or Hct <33% High
    IV Stage 0-III with platelets <100 x 109/L High
    1Used in the modified Rai classification
Binet System
  • Based on the number of areas with lymph nodes >1 cm in diameter or organomegaly, and the presence of anemia or thrombocytopenia
  • Involved areas include head and neck, axilla, groins including superficial femorals, spleen, and liver
    Stage Description
    A Hgb ≥10 g/dL, platelets ≥100,000/mm3, and <3 enlarged areas
    Hgb ≥10 g/dL, platelets ≥100,000/mm3, and ≥3 enlarged areas
    C Hgb <10 g/dL, and/or platelets <100,000/mm3, and any number of enlarged areas

Functional Status

  • Used to assess how a disease affects the daily activities of a patient
  • Commonly used performance status scoring systems:
    • Karnofsky performance status scale
    • Eastern Cooperative Oncology Group (ECOG) performance scale

Physical Examination

  • Node-bearing areas (eg Waldeyer’s ring)
  • Spleen, liver enlargement
  • Skin examination: Presence of macules, papules, plaques, nodules, ulcers, blisters

Laboratory Tests

Essential Tests
  • Complete blood count, with differential and platelet count
  • Metabolic panel, including lactate dehydrogenase (LDH) levels and serum beta-2-microglobulin
  • Bilirubin, haptoglobulin
  • Direct Coomb’s test/direct antiglobulin test - may help predict autoimmune hemolytic anemia
  • Hepatitis B screening - if considering CD20 monoclonal antibody therapy
Optional Tests
  • Serum uric acid levels
  • Quantitative serum immunoglobulin test - to determine patient’s immunological status
  • Testing for hepatitis C, cytomegalovirus (CMV) and human immunodeficiency virus (HIV) is also suggested
Molecular and Genetic Analysis
  • Effectively differentiates chronic lymphocytic leukemia (CLL) from other forms of leukemia by identifying the specific cell lineage using antibodies

Immunophenotyping by Flow Cytometry

  • Fast and reliable method of identifying single cell populations of surface antigens
  • Uses antibodies/markers to identify the presence and proportion of surface antigens
    • B-cell associated antigens: CD19, CD20 (low), CD23
    • T-cell antigen: CD5
    • Surface immunoglobulins: IgM, IgD (low)
  • Used for confirmation of clonality of B cells

Fluorescence in situ Hybridization (FISH)

  • Detects del(17p), del(11q), del(13q), and trisomy 12

TP53 and Immunoglobulin Heavy Chain (IGHV) Gene Mutation Analysis by Sequencing

  • Commonly used for determination of the patient’s prognosis and to help in selecting the best treatment option


  • Optional diagnostic test when diagnosis cannot be established with flow cytometry alone

Lymph Node Biopsy

  • May be used to rule out other types of lymphoproliferative diseases and high grade lymphoma transformation in suspected cases

Bone Marrow Biopsy

  • Optional test used to ascertain the nature of cytopenias (anemia, thrombocytopenia) pre- and post-treatment

Lumbar Puncture

  • May be used for patients with possible central nervous system (CNS) involvement with overt symptoms


  • Imaging studies are not routinely used

Computed Tomography (CT)

  • Used to assess tumor load and for the assessment of symptoms
  • Also used for baseline assessment of patients enrolled in clinical trials

Positron Emission Tomography (PET)

  • Recommended for localized diseases and to identify occult sites of the disease or histologic transformation


  • May be considered for the detection of lymphadenopathies and organ enlargement


Prognostic Markers
  • Aids in predicting survival or disease progression beyond clinical staging
  • Includes serum markers (CD23, thymidine kinase, serum β2-microglobulin [B2M]), genetic markers (immunoglobulin heavy chain variable [IGHV] gene analysis) and tests for genomic abnormalities (CD38 expression, CD49d and ZAP-70 expression or methylation)
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