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This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
The Bottom Line
- Commonest leukaemia in adults in Western countries — median age at diagnosis 72 years. More common in males (2:1)
- Often diagnosed incidentally: persistent lymphocytosis (>5 × 10⁹/L) on routine FBC with smudge cells on film
- Staging: Binet (A/B/C) or Rai system. Stage A (most patients at diagnosis) — no treatment needed, watch and wait
- Treatment indications: progressive symptoms (B symptoms, fatigue), progressive lymphadenopathy/splenomegaly, marrow failure (anaemia or thrombocytopenia)
- First-line treatment (most patients): targeted therapy with BTK inhibitors (ibrutinib/acalabrutinib) or venetoclax + obinutuzumab. FCR chemo-immunotherapy for young fit patients with mutated IGHV
Overview
Chronic lymphocytic leukaemia (CLL) is a clonal malignancy of mature B-lymphocytes that accumulate in the blood, bone marrow, lymph nodes, and spleen. CLL and small lymphocytic lymphoma (SLL) are considered the same disease — CLL when primarily leukaemic (blood), SLL when predominantly nodal. The disease is heterogeneous: some patients have stable disease for decades without requiring treatment, while others progress rapidly. Prognostic markers include IGHV mutation status, TP53 deletion/mutation, and cytogenetic abnormalities.
Epidemiology
CLL is the most common leukaemia in adults in the UK and Western world, with approximately 3,500 new cases per year in the UK. The median age at diagnosis is 72 years, and it is twice as common in men. It is exceedingly rare in East Asian populations. First-degree relatives of CLL patients have a 6-9 fold increased risk. Approximately 30-50% of patients are diagnosed incidentally from routine blood tests.
Clinical Features
Symptoms
Often asymptomatic — incidental lymphocytosis on routine FBC
Painless lymphadenopathy — often generalised
Fatigue and reduced exercise tolerance
Recurrent infections (immune deficiency from hypogammaglobulinaemia)
B symptoms: weight loss >10%, drenching night sweats, fever (suggest progressive disease)
Autoimmune complications: symptoms of haemolytic anaemia or ITP
Signs
Painless, non-tender lymphadenopathy — often symmetrical and generalised
Splenomegaly (50-60% of patients at some point)
Hepatomegaly (less common)
Signs of anaemia (if marrow failure or autoimmune haemolysis)
Skin infiltration (rare)
Investigations
First-line
FBCPersistent lymphocytosis >5 × 10⁹/L for >3 months. Often very high counts (30-200+). Hb and platelets normal early; low = advanced disease (Binet C)
Blood filmMature small lymphocytes with SMUDGE CELLS (fragile CLL cells disrupted during preparation) — classic exam finding
Immunophenotyping (flow cytometry)Diagnostic: CD5+, CD19+, CD23+ B-cells with weak surface immunoglobulin. CLL score (Matutes score) ≥4/5 = CLL
Second-line
ImmunoglobulinsHypogammaglobulinaemia common — explains recurrent infections. Consider IV immunoglobulin replacement if recurrent severe infections
DAT (Coombs test)Positive in ~10-25% — autoimmune haemolytic anaemia is a recognised complication
LDH, beta-2-microglobulinTumour burden markers; raised B2M = poorer prognosis
Specialist
FISH cytogeneticsPrognostic: del(13q) = good prognosis. del(11q) = intermediate. del(17p)/TP53 mutation = poor prognosis (resists chemo-immunotherapy)
IGHV mutation statusMutated IGHV = favourable prognosis, responds well to FCR. Unmutated IGHV = poorer prognosis, favours targeted therapy
CT scanFor staging and assessing lymphadenopathy/organomegaly when treatment is being considered
1
Watch and wait (Binet A, asymptomatic)
- No treatment needed for early-stage asymptomatic CLL
- Regular monitoring: FBC every 3-6 months
- Most patients at diagnosis fall into this category and may never need treatment
- Explain that CLL is a chronic condition and early treatment does NOT improve survival
2
Treatment indications
- Progressive marrow failure: Hb <100 g/L or platelets <100 × 10⁹/L (Binet C)
- Progressive/symptomatic lymphadenopathy or splenomegaly
- Constitutional symptoms (B symptoms)
- Progressive lymphocytosis (doubling time <6 months)
- Autoimmune cytopenias not responding to steroids
3
First-line treatment
- Del(17p) or TP53 mutation: ibrutinib (BTK inhibitor) or venetoclax + obinutuzumab — do NOT use chemo-immunotherapy (refractory)
- Fit patients with mutated IGHV, no del(17p): FCR (fludarabine, cyclophosphamide, rituximab) — potential for long-term remission
- Most other patients: BTK inhibitor (ibrutinib or acalabrutinib) or venetoclax + obinutuzumab — now preferred over FCR for unmutated IGHV
4
Supportive care
- Infection prevention: annual influenza and pneumococcal vaccination
- IV immunoglobulin if hypogammaglobulinaemia with recurrent infections
- Autoimmune complications (AIHA, ITP): steroids first-line, rituximab second-line
Complications
- Richter transformation: Transformation to aggressive diffuse large B-cell lymphoma in 5-10% — suspect if sudden clinical deterioration, rising LDH, new bulky lymphadenopathy, B symptoms. Median survival ~1 year
- Autoimmune cytopenias: AIHA (~10%), ITP (~5%), pure red cell aplasia — treat with steroids
- Recurrent infections: Hypogammaglobulinaemia + neutropenia (treatment-related). Herpes zoster reactivation common with BTK inhibitors
- Secondary malignancies: Increased risk of solid tumours and other haematological malignancies
UKMLA Exam Tips
- 1Incidental persistent lymphocytosis + smudge cells on film in an elderly patient = CLL until proven otherwise
- 2CD5+ B-cell — the key immunophenotypic finding. B-cells are normally CD5-negative; CLL is the exception
- 3Watch and wait for Binet A — early treatment does NOT improve survival in asymptomatic early-stage CLL
- 4Del(17p)/TP53 mutation = chemo-resistant. Must use targeted therapy (ibrutinib, venetoclax)
- 5Richter transformation: sudden clinical deterioration + rising LDH + new bulky nodes in a CLL patient — urgent biopsy
- 6Warm AIHA complicating CLL: DAT positive, treat with steroids — a classic exam scenario
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