Key Facts

Chronic lymphocytic leukaemia (CLL) is a low-grade B-cell lymphoproliferative disorder characterised by progressive accumulation of functionally incompetent monoclonal B lymphocytes in the blood, bone marrow, and lymphoid tissues.

Epidemiology

• Most common leukaemia in Western countries: ~3,500/year in UK
• Median age: ~72 years; rare <40
• Male:female 2:1

Aetiology

• Unknown; familial clustering (5–10× risk in first-degree relatives)
• NOT associated with radiation or benzene (unlike other leukaemias)

Pathophysiology

• Clonal expansion of mature CD5+ B cells that accumulate due to defective apoptosis (overexpression of BCL-2)
• Cells are immunologically incompetent → hypogammaglobulinaemia → recurrent infections
• Autoimmune phenomena: AIHA (~10%), ITP (~5%)
• Microenvironment interactions promote CLL cell survival

Often Asymptomatic

• Incidental lymphocytosis on routine FBC (~80% at diagnosis)

Symptomatic

• Lymphadenopathy: painless, symmetrical, rubbery
• Splenomegaly (~50%)
• Hepatomegaly (~15%)
• B symptoms: weight loss >10%, drenching night sweats, fever >38°C
• Recurrent infections: hypogammaglobulinaemia (sinopulmonary)
• Autoimmune: AIHA (warm), ITP

Red Flags

• Richter transformation: rapid lymph node enlargement, B symptoms, rising LDH
• Severe autoimmune cytopenias
• Recurrent severe infections

Bloods

• FBC: lymphocytosis ≥5 × 10⁹/L (often 20–100+)
• Blood film: small mature lymphocytes, smudge/smear cells
• Flow cytometry: CD5+, CD19+, CD23+, weak sIg — CLL immunophenotype score (≥4/5 = CLL)
• Immunoglobulins: often low (hypogammaglobulinaemia)
• DAT: if AIHA suspected
• LDH, β2-microglobulin: prognostic markers

Prognostic

• IGHV mutation status: mutated (good prognosis); unmutated (poor)
• Cytogenetics (FISH): del(13q) = good; trisomy 12 = intermediate; del(11q) = poor; del(17p)/TP53 mutation = very poor (resistant to FCR)
• TP53 mutation analysis: critical for treatment decisions

Staging

• Binet staging (Europe): A (lymphocytosis ± ≤2 areas), B (≥3 lymphoid areas), C (anaemia/thrombocytopenia)
• Rai staging (USA): 0–IV
• Bone marrow biopsy and CT: not routinely needed for diagnosis; used if treatment planned

Watch and Wait (Binet A/B asymptomatic)

• NO treatment benefit from early intervention
• Monitor FBC every 3–6 months
• Treat only when indications arise

Treatment Indications

• Progressive marrow failure (Hb <100, platelets <100)
• Massive/progressive lymphadenopathy (>10cm) or splenomegaly
• Constitutional symptoms (B symptoms)
• Lymphocyte doubling time <6 months
• Autoimmune cytopenias not responding to steroids

First-line Treatment

Del(17p)/TP53:

• Ibrutinib (BTK inhibitor; continuous) or venetoclax + obinutuzumab (fixed duration; NICE TA663)

Without del(17p)/TP53:

• Ibrutinib (NICE TA689) or venetoclax + obinutuzumab
• FCR (fludarabine, cyclophosphamide, rituximab): young, fit, IGHV mutated (potential cure for some; ~60% 10-year PFS)

Supportive

• Immunoglobulin replacement: if hypogammaglobulinaemia with recurrent infections
• Vaccination: annual influenza, pneumococcal, COVID (response may be impaired)
• Infection prophylaxis: aciclovir (herpes), co-trimoxazole (PCP) during/after treatment

Referral Criteria

• Haematology: all confirmed CLL
• Urgent: Richter transformation, severe cytopenias

• Highly variable: early stage may never need treatment; median survival Binet A >10 years
• Binet C: median survival ~3–5 years (improving with novel agents)
• IGHV mutated: ~85% 10-year survival
• Del(17p)/TP53: historically very poor (~2–3 years); improved with ibrutinib/venetoclax (~60–70% 5-year)
• FCR in young IGHV mutated: potential cure (~60% 10-year PFS)
• Richter transformation: median survival ~6–12 months
• Novel agents (BTK inhibitors, BCL-2 inhibitors): transforming CLL outcomes

Binet Staging