What is chronic lymphocytic leukemia?

What is Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia is a malignant B-cell disorder characterized by the progressive accumulation of morphologically mature but functionally abnormal clonal B lymphocytes in the blood, bone marrow, and lymphoid tissues, driven by specific genomic alterations that disrupt normal apoptosis and proliferation pathways. 1, 2

Epidemiology and Demographics

• CLL is the most common leukemia in Western countries, with an incidence of 4.2 per 100,000 per year, rising to over 30 per 100,000 per year in patients older than 80 years 3
• The median age at diagnosis is 72 years, though approximately 10% of patients are younger than 55 years at presentation 3

Diagnostic Criteria

The diagnosis requires ≥5,000 monoclonal B lymphocytes per microliter in peripheral blood sustained for at least 3 months, confirmed by flow cytometry. 3, 4, 5

Morphologic Features

• Blood smears show predominantly small, mature-appearing lymphocytes with narrow cytoplasm borders and dense nuclei lacking discernible nucleoli with partially aggregated chromatin 3, 4
• Admixtures of larger or atypical cells including prolymphocytes are commonly present (up to 55% prolymphocytes is still consistent with CLL; above this threshold suggests prolymphocytic leukemia) 4
• Smudge cells (nuclear shadows from ruptured lymphocytes) are characteristic morphologic features on blood smears 6

Immunophenotype

CLL cells co-express CD5 (normally a T-cell marker) along with B-cell surface antigens CD19, CD20, and CD23, with characteristically low levels of surface immunoglobulin, CD20, and CD79b compared to normal B cells. 3, 4

• Each clone is restricted to expression of either kappa or lambda immunoglobulin light chains, confirming monoclonality 3

Critical Diagnostic Pitfall

Mantle cell lymphoma must be excluded, as it can appear morphologically similar but requires entirely different management—mantle cell lymphoma typically does not express CD23, and cyclin D1 staining or FISH for t(11;14) translocation is essential to distinguish it from CLL. 3, 4

Pathogenesis

• The disease is initiated by specific genomic alterations that interfere with regulation of proliferation and apoptosis, as well as signal transduction through the B-cell receptor and interactions with the tumor microenvironment 1, 2
• Key genetic alterations include del(17p), TP53 mutations, del(11q), and IGHV mutational status, which significantly impact prognosis and treatment selection 1, 7

Clinical Heterogeneity

CLL displays immense clinical heterogeneity—many patients have indolent disease not requiring intervention for years, while others present with aggressive, symptomatic leukemia requiring immediate treatment. 8

• Treatment is indicated only for patients with active or symptomatic disease, not based on lymphocyte count alone 1, 7, 2
• The disease is treatable but not curable with current standard therapies, though novel targeted agents are changing the treatment landscape 7, 2