What is Chronic Lymphocytic Leukemia (CLL)?

Chronic Lymphocytic Leukemia (CLL)

Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in Western countries, characterized by the accumulation of small, mature-appearing B lymphocytes in the blood, bone marrow, and lymphoid tissues. 1

Definition and Diagnosis

CLL is diagnosed based on the following criteria:

• Presence of ≥5,000 B lymphocytes/μL (5 × 10^9/L) in peripheral blood for at least 3 months 2
• Clonality of circulating B lymphocytes confirmed by flow cytometry 2
• Characteristic immunophenotype: CD5+, CD19+, CD20+ (low), CD23+, with low expression of surface immunoglobulin, CD20, and CD79b 2
• Restriction to either κ or λ immunoglobulin light chains 2

The leukemic cells appear morphologically as small, mature lymphocytes with narrow cytoplasm, dense nucleus lacking discernible nucleoli, and partially aggregated chromatin 2. Gumprecht nuclear shadows or "smudge cells" are also characteristic findings 2.

CLL vs. Small Lymphocytic Lymphoma (SLL)

CLL and SLL are different manifestations of the same disease:

• CLL: Significant number of abnormal lymphocytes in peripheral blood (≥5,000/μL), bone marrow, and lymphoid tissues 2
• SLL: Bulk of disease in lymph nodes and bone marrow, with <5,000 B lymphocytes/μL in peripheral blood 2

SLL diagnosis requires lymphadenopathy and/or splenomegaly, and should be confirmed by lymph node biopsy whenever possible 2.

Epidemiology

• Incidence: 4.2/100,000/year in Western countries 2
• Increases to >30/100,000/year after age 80 2
• Median age at diagnosis: 69-72 years 2
• About 10-14% of patients are younger than 55 years 2

Staging and Risk Assessment

Two clinical staging systems are commonly used:

Binet Staging System (Europe)

• Stage A: Hemoglobin ≥10 g/dL, platelets ≥100 × 10^9/L, <3 lymph node regions (median survival >10 years) 2
• Stage B: Hemoglobin ≥10 g/dL, platelets ≥100 × 10^9/L, ≥3 lymph node regions (median survival 7 years) 2
• Stage C: Hemoglobin <10 g/dL, platelets <100 × 10^9/L (median survival 1.5-2.5 years) 2

Rai Staging System (US)

• High Risk (Rai III-IV): Lymphocytosis with anemia (Hb <11 g/dL) and/or thrombocytopenia (platelets <100 × 10^9/L) (median survival 1.5-3 years) 2

Prognostic Factors

Several factors affect prognosis:

• Cytogenetic abnormalities (especially del(17p) and del(11q)) 2, 1
• TP53 mutations 1
• IGHV mutation status 1
• CD38 and ZAP70 expression 2

Recommended Initial Evaluation

• Complete blood count with differential 2
• Peripheral blood flow cytometry 2
• FISH analysis for cytogenetic abnormalities (especially del(17p)) before starting therapy 2
• Bone marrow biopsy (not required for diagnosis but recommended before initiating myelosuppressive therapies) 2
• Serum chemistry including LDH, bilirubin, serum immunoglobulin, direct antiglobulin test (DAT) 2
• Evaluation of relevant infections (hepatitis B and C, CMV, HIV) prior to chemoimmunotherapy 2

Treatment Approach

Treatment is not indicated for all patients at diagnosis. The standard approach for early-stage, asymptomatic disease is "watch and wait" with regular monitoring 2.

Treatment is indicated for patients with:

• Active disease as defined by iwCLL criteria
• Advanced Binet (B or C) or Rai (III-IV) stages
• Disease-related symptoms (B symptoms: fever, night sweats, weight loss)
• Progressive lymphadenopathy, hepatosplenomegaly
• Cytopenias due to bone marrow involvement

First-line Treatment Options

For patients requiring treatment, options include:

• BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) 3, 4
• BCL2 inhibitor (venetoclax) in combination with anti-CD20 antibodies 4
• Chemoimmunotherapy with rituximab-based regimens in select patients 5

For patients with del(17p) or TP53 mutations, BTK inhibitors are preferred 4.

Common Pitfalls in Diagnosis

• Failure to distinguish CLL from other CD5+ B-cell lymphomas, particularly mantle cell lymphoma (which is typically CD23-) 2
• Not confirming SLL diagnosis with lymph node biopsy when possible 2
• Overlooking the need for cytogenetic and molecular testing before treatment 2
• Confusing monoclonal B-lymphocytosis (MBL) with CLL (MBL has <5,000 B lymphocytes/μL without lymphadenopathy or other clinical features) 2

CLL remains an incurable but highly treatable disease with a variable clinical course. Advances in understanding its biology have led to targeted therapies that have significantly improved outcomes, particularly for high-risk patients.