Definition of Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is defined by the presence of ≥5,000 monoclonal B lymphocytes per microliter in peripheral blood sustained for at least 3 months, with a characteristic immunophenotype of CD5+, CD19+, CD20+ (low), CD23+, surface immunoglobulin (low), and CD79b (low). 1, 2
Diagnostic Criteria and Lymphocyte Phenotype
The diagnosis requires confirmation of clonality by flow cytometry, which demonstrates restriction to either kappa or lambda immunoglobulin light chains 1. The leukemic cells appear morphologically as small, mature lymphocytes with a narrow cytoplasmic border and dense nucleus lacking discernible nucleoli, with partially aggregated chromatin 1.
Key immunophenotypic features that distinguish CLL from other lymphoproliferative disorders:
- Co-expression of CD5 (a T-cell antigen) with B-cell markers (CD19, CD20, CD23) 1
- Characteristically low levels of surface immunoglobulin, CD20, and CD79b compared to normal B cells 1
- Typically negative for FMC7 1
Critical distinction: Mantle cell lymphoma also expresses CD5 and B-cell antigens but generally does not express CD23, making this a key differentiating feature 1.
Duration of Lymphocytosis
The lymphocytosis must persist for a minimum of 3 months to establish the diagnosis of CLL 1, 3. This duration requirement distinguishes CLL from transient lymphocytosis due to other causes. The median lymphocyte count at diagnosis is typically 20-30 × 10⁹/L 4.
Epidemiology
CLL is the most common adult leukemia in Western countries, representing approximately 25% of all adult leukemias 1, 2, 5.
Incidence patterns:
- Overall incidence: 4-4.2 per 100,000 per year in the Western world 1
- Dramatically increases with age: >30-50 per 100,000 per year in patients over 70-80 years 1
- Median age at diagnosis: 69-72 years 1, 3
- Approximately 10-14% of patients are younger than 55 years at diagnosis 1
Genetic susceptibility: There is a 6- to 9-fold increased risk for family members of CLL patients, indicating inherited genetic predisposition 1.
Sites of Involvement
CLL is characterized by progressive accumulation of leukemic cells in multiple anatomic compartments:
- Peripheral blood: The defining feature, with sustained lymphocytosis 5, 6
- Bone marrow: Infiltration is characteristic and can cause cytopenias 1, 5, 6
- Lymph nodes: Lymphadenopathy is common and used in staging systems 1, 5, 6
- Spleen: Splenomegaly occurs frequently 5, 6, 4
- Liver: Hepatomegaly may be present 1
- Other lymphoid tissues: General lymphoid tissue involvement is typical 1, 5
Relationship to Small Lymphocytic Lymphoma (SLL)
CLL and SLL are the same disease entity with different presentations 2, 3. The distinction is based solely on the distribution of disease:
- CLL: ≥5 × 10⁹/L B lymphocytes in peripheral blood 1, 2
- SLL: <5 × 10⁹/L B lymphocytes in peripheral blood with lymphadenopathy and/or splenomegaly 1, 2
Both conditions share the identical immunophenotype and are managed identically 1, 2, 3. SLL constitutes approximately 7% of newly diagnosed non-Hodgkin's lymphomas 2.
Clinical Heterogeneity
The disease demonstrates immense clinical heterogeneity, with some patients experiencing indolent disease not requiring treatment for many years, while others present with aggressive, symptomatic leukemia requiring immediate intervention 6, 7. In approximately half of patients, the lymphocyte count doubles over 1 year, while in others it may remain stable for years 4.