What Is Chronic Lymphocytic Leukemia (CLL)?
Chronic lymphocytic leukemia (CLL) is a malignancy characterized by the progressive accumulation of small, mature-appearing B lymphocytes in the peripheral blood, bone marrow, and lymphoid tissues, defined by the presence of ≥5,000 monoclonal B lymphocytes/μL in peripheral blood sustained for at least 3 months. 1, 2
Disease Classification and Epidemiology
CLL is the most common adult leukemia in Western countries, representing approximately 25% of all adult leukemias, with an incidence of 4:100,000/year that increases to >30:100,000/year in patients over 80 years of age 1, 2, 3
CLL and small lymphocytic lymphoma (SLL) are the same disease entity, distinguished only by the location of abnormal lymphocytes: CLL when predominantly in blood (≥5×10⁹/L B lymphocytes) and SLL when predominantly in lymph nodes (<5×10⁹/L B lymphocytes with lymphadenopathy) 1, 2
The median age at diagnosis is 69 years, with 14% of patients younger than 55 years 1
Cellular and Morphologic Characteristics
The leukemic cells are small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli, with partially aggregated chromatin 1
CLL results from impaired apoptosis of clonal B-cells initiated by specific genomic alterations, leading to progressive accumulation rather than rapid proliferation 4, 3
Blood smears characteristically show "smudge cells" or Gumprecht cells (nuclear shadows) due to the fragility of CLL lymphocytes 5
Diagnostic Criteria
The diagnosis requires three key elements:
≥5,000 monoclonal B lymphocytes/μL in peripheral blood sustained for at least 3 months 1, 2
Confirmation of B-cell clonality by flow cytometry demonstrating the characteristic immunophenotype 1
Specific immunophenotype: CD5+, CD19+, CD20+ (low), CD23+, with low surface immunoglobulin expression and restriction to either kappa or lambda light chains 1, 2
Important Diagnostic Distinctions
Bone marrow biopsy is not required for diagnosis; flow cytometry of peripheral blood is sufficient 1, 2
Mantle cell lymphoma must be excluded, as it also expresses CD5 and B-cell markers but typically does not express CD23 and shows t(11;14) or cyclin D1 positivity 1
Monoclonal B lymphocytosis (MBL) is diagnosed when <5,000 B cells/μL are present without lymphadenopathy or other features of lymphoproliferative disorder, with progression to CLL occurring at approximately 1.1% per year 1
Clinical Presentation and Course
Many patients are asymptomatic at diagnosis, with disease discovered incidentally on routine blood work 6
Symptomatic patients may present with lymphadenopathy, splenomegaly, hepatomegaly, or constitutional symptoms 5, 6
The clinical course is highly variable: some patients have indolent disease with long survival, while others experience aggressive disease requiring early treatment 3, 7, 6
Prognostic Factors
Key prognostic markers include:
Deletion 17p [del(17p)] and/or TP53 mutations predict resistance to chemoimmunotherapy and shorter time to progression with most therapies 1, 3, 7
IGHV (immunoglobulin heavy-chain variable region gene) mutation status: mutated IGHV indicates better prognosis 1, 3
The CLL International Prognostic Index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups 3, 7
Staging Systems
Two equivalent staging systems are used:
Binet staging (European): Stage A (<3 lymph node regions, Hb ≥10 g/dL, platelets ≥100×10⁹/L) has median survival >10 years; Stage C (Hb <10 g/dL or platelets <100×10⁹/L) has median survival 1.5-2.5 years 1
Rai staging (American): Stage 0-II are lower risk; Stages III-IV (anemia or thrombocytopenia) indicate higher risk 1