What is chronic lymphocytic leukemia (CLL)?

What is Chronic Lymphocytic Leukemia (CLL)?

Chronic lymphocytic leukemia (CLL) is a malignancy characterized by the progressive accumulation of small, mature-appearing monoclonal B lymphocytes primarily in the peripheral blood, bone marrow, and lymphoid tissues. 1, 2

Epidemiology

• CLL is the most common leukemia in adults in Western countries, representing approximately 25% of all adult leukemias 1, 3
• The incidence is 4 per 100,000 per year in the general population, but increases dramatically to >30-50 per 100,000 per year after age 70-80 years 1
• The median age at diagnosis is 69-72 years, though 11-14% of patients are younger than 55 years 1, 3

Pathophysiology

• The disease results from specific genomic alterations that impair apoptosis and interfere with the regulation of proliferation in clonal B-cells 4, 5
• CLL cells accumulate rather than rapidly proliferate, distinguishing it from acute leukemias 6
• Signaling via the B-cell receptor and interactions with stromal cells, T cells, and nurse-like cells in lymph nodes contribute to disease pathogenesis 6

Diagnostic Criteria

The diagnosis requires ≥5,000 B lymphocytes/µL (≥5×10⁹/L) in peripheral blood sustained for at least 3 months, confirmed by flow cytometry. 1, 2, 7

Key Diagnostic Features:

• Morphology: Small, mature-appearing lymphocytes with narrow cytoplasm, dense nucleus lacking discernible nucleoli, and partially aggregated chromatin 1
• Immunophenotype: The characteristic pattern is CD5+, CD19+, CD20+ (low expression), CD23+, surface immunoglobulin low, CD79b low, and FMC7 negative 1, 7
• Clonality: Each clone expresses either kappa or lambda immunoglobulin light chains (not both), confirming monoclonality 1
• Flow cytometry of peripheral blood alone is usually sufficient for diagnosis—bone marrow biopsy is not required for diagnosis 1, 2

Relationship to Small Lymphocytic Lymphoma (SLL)

• CLL and SLL are the same disease entity with different presentations 2, 3
• SLL is diagnosed when there is lymphadenopathy and/or splenomegaly with <5×10⁹/L B lymphocytes in peripheral blood 1, 2
• Both share the identical immunophenotype and are managed identically 2
• The distinction does not affect treatment decisions or staging systems 2

Clinical Course and Prognosis

• The clinical progression is highly heterogeneous, ranging from patients requiring immediate treatment to those who never need therapy 4, 6
• Median survival varies from 1.5 years to >10 years depending on initial stage 1
• Two staging systems are used: Binet (stages A, B, C) in Europe and Rai (stages 0-IV) in North America 1

Binet Staging:

• Stage A: <3 lymph node regions involved, hemoglobin ≥10 g/dL, platelets ≥100×10⁹/L (median survival >10 years) 1
• Stage B: ≥3 lymph node regions involved, hemoglobin ≥10 g/dL, platelets ≥100×10⁹/L (median survival 7 years) 1
• Stage C: Hemoglobin <10 g/dL or platelets <100×10⁹/L regardless of lymph node involvement (median survival 1.5-2.5 years) 1

Important Prognostic Factors

• Deletion 17p [del(17p)] and/or TP53 mutations predict resistance to chemoimmunotherapy and shorter time to progression with most targeted therapies 1, 4, 5
• FISH analysis is recommended before starting therapy to detect del(17p) and other cytogenetic abnormalities 1
• IGHV mutational status helps predict time to progression, with unmutated IGHV indicating more aggressive disease 1, 3
• The CLL International Prognostic Index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups 4, 5

Common Pitfalls

• Do not confuse CLL with mantle cell lymphoma: Mantle cell lymphoma also expresses CD5 and B-cell markers but typically does not express CD23 and has t(11;14) translocation 1
• Do not treat based on lymphocyte count alone: Even markedly elevated white blood cell counts rarely cause symptoms in CLL, and absolute lymphocyte count should not be the sole indicator for treatment 7
• Do not order unnecessary bone marrow biopsies: Bone marrow biopsy is only recommended before initiating myelosuppressive therapies or for evaluating unclear cytopenias, not for diagnosis 1