Chronic lymphocytic leukemia (CLL)

Definition

Chronic lymphocytic leukemia (CLL) is a neoplasm of mature-appearing, monoclonal B lymphocytes that accumulate in the blood, bone marrow, lymph nodes, and spleen. CLL and small lymphocytic lymphoma (SLL) are regarded as one disease with different distribution. Its precursor is monoclonal B-cell lymphocytosis (MBL).

Classification

Binet stages (sites assessed: cervical, axillary, and inguinal lymph nodes, liver, spleen):

• Binet A: ≤ 2 involved sites, hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/µL
• Binet B: 3–5 involved sites, hemoglobin and platelets as in stage A
• Binet C: hemoglobin < 10 g/dL or platelets < 100,000/µL, regardless of the number of involved sites

Rai stages: 0 lymphocytosis; I plus lymph node enlargement; II plus hepatomegaly or splenomegaly; III plus anemia (hemoglobin < 11 g/dL); IV plus thrombocytopenia (< 100,000/µL).

MBL according to WHO 2022: clonal B cells < 0.5 × 10⁹/L (low-count MBL) or ≥ 0.5 × 10⁹/L with total B cells < 5 × 10⁹/L (CLL/SLL-type MBL), each without other features of CLL.

Occurrence & epidemiology

CLL is the most common type of leukemia in the Western world. In Germany, according to the RKI, a good third of newly diagnosed leukemias are CLL. The average age at diagnosis is about 70 years; the disease is extremely rare in children. It is rare in Japan and China and more common in people of Ashkenazi Jewish ancestry.

Aetiopathogenesis

CD5-positive B cells acquire mutations, become continuously activated, and first form MBL; further genetic abnormalities lead to CLL. About 1–2 % of MBL progresses to CLL per year. A hereditary component is likely in some cases. Recurrent genetic abnormalities include del(13q), del(11q), del(17p), and trisomy 12, as well as TP53 mutations.

Clinical features

• Often asymptomatic initially; diagnosis frequently follows an incidental finding of lymphocytosis.
• Nonspecific complaints: fatigue, weakness, anorexia, weight loss, fever, night sweats, early satiety.
• Lymphadenopathy in more than 50 %, localized (mostly cervical and supraclavicular) or generalized; splenomegaly and hepatomegaly less common.
• Susceptibility to infection due to hypogammaglobulinemia, which develops in up to two-thirds.
• Autoimmune phenomena: autoimmune hemolytic anemia (positive direct antiglobulin test) and immune thrombocytopenia.
• Richter transformation into diffuse large B-cell lymphoma in about 2–10 %.

Diagnosis

• Blood count: absolute lymphocytosis above 5,000/µL raises suspicion of CLL.
• Flow cytometry of blood: demonstrates clonality; coexpression of CD5, CD19, CD20, and CD23 with light chain restriction (kappa or lambda) is typical.
• Bone marrow examination is not required for diagnosis; if performed, often more than 30 % lymphocytes.
• Other findings: hypogammaglobulinemia, elevated LDH, uric acid, and liver enzymes, rarely hypercalcemia.
• Cytogenetics and molecular genetics from blood (e.g., FISH for del(17p), TP53 mutation, IGHV mutation status) for risk assessment.

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Further reading (open access)

1. MSD Manual Professional: Chronic Lymphocytic Leukemia (CLL)
2. Alaggio et al., Leukemia 2022: WHO-Klassifikation (5. Aufl.), lymphatische Neoplasien (PMC-Volltext)
3. RKI, Zentrum für Krebsregisterdaten: Leukämien

Cross-references