Chronic Lymphocytic leukaemia (CLL) ✅

Related Subjects: |Leukaemias in General |Acute Promyelocytic Leukaemia |Acute Myeloblastic Leukaemia (AML) |Acute Lymphoblastic Leukaemia (ALL) |Chronic Lymphocytic leukaemia (CLL) |Chronic Myeloid Leukaemia (CML) |Hairy Cell Leukaemia |Differentiation syndrome |Tretinoin (All-trans-retinoic acid (ATRA) ) |Haemolytic anaemia |Immune(Idiopathic) Thrombocytopenic Purpura (ITP)

Chronic Lymphocytic Leukaemia (CLL) is the most common leukaemia in adults, characterized by a slow-growing, typically benign malignant clone of mature B lymphocytes. It is commonly complicated by secondary immunodeficiency (panhypogammaglobulinaemia). While prophylactic IV immunoglobulin can prevent recurrent infections in severe cases, it does not prolong survival.

ℹ️ About & Pathophysiology

• CLL is an indolent (slow-growing) lymphoproliferative disorder of mature B cells.
• The malignant B cells accumulate in the blood, bone marrow, lymph nodes, and spleen.
• These cells are functionally incompetent, leading to immunodeficiency.
• Smear cells (smudge cells) are a classic finding on blood films because the leukaemic cells are fragile and burst during slide preparation.

🧬 Aetiology & Epidemiology

• The most common form of leukaemia in adults in Western countries.
• Primarily affects older individuals (median age at diagnosis is \~70 years); rare under 40.
• More common in males (2:1 ratio).
• Often detected incidentally through routine blood tests showing a raised white cell count (WCC).

🩺 Clinical Features

• Asymptomatic: Up to 70% of patients are asymptomatic at diagnosis.
• Lymphadenopathy: Painless, symmetrical, rubbery lymph node enlargement (cervical, axillary, inguinal).
• Organomegaly: Hepatosplenomegaly causing early satiety or abdominal discomfort.
• Bone Marrow Failure: Anaemia (fatigue, pallor) and thrombocytopenia (bruising, bleeding) in advanced stages.
• B-Symptoms: Unintentional weight loss (>10% in 6 months), severe fatigue, drenching night sweats, or unexplained fever.
• Recurrent Infections: Due to hypogammaglobulinaemia (e.g., recurrent chest infections, shingles).
• Autoimmune Cytopenias: Autoimmune Haemolytic Anaemia (AIHA) or Immune Thrombocytopenia (ITP) occur in 5–10% of patients.

⚠️ Complications

• Richter's Transformation: Transformation of CLL into a high-grade aggressive lymphoma (usually Diffuse Large B-Cell Lymphoma, DLBCL). Occurs in 2–10% of cases and carries a poor prognosis. Sudden, rapid lymph node growth is a red flag.
• Secondary Malignancies: Increased risk of skin cancers (melanoma and non-melanoma) due to immune dysregulation.

🔎 Investigations

• Full Blood Count (FBC): Lymphocytosis (often > 15 × 10&sup9;/L). Hb and platelets may be normal initially but fall as disease progresses.
• Blood Film: Predominance of small, mature-looking lymphocytes and classic smear/smudge cells.
• Flow Cytometry (Immunophenotyping): Essential for diagnosis. Confirms a monoclonal B-cell population expressing CD19, CD5, and CD23 (CD5 is normally a T-cell marker, making its presence on B-cells highly suggestive of CLL).
• Direct Antiglobulin Test (DAT / Coombs Test): To check for autoimmune haemolytic anaemia if Hb is dropping.
• Serum Immunoglobulins: Often shows reduced IgG, IgA, and IgM (hypogammaglobulinaemia).
• Cytogenetics / FISH: Crucial for guiding treatment.
  • del(17p) or TP53 mutation: Poor prognosis; resistant to standard chemotherapy.
  • del(13q): Good prognosis if isolated.
  • IGHV mutation status: Mutated IGHV indicates a better prognosis; unmutated indicates a more aggressive course.

⚖️ Differential Diagnosis

• Mantle Cell Lymphoma: Also CD5+, but typically CD23 negative and has the t(11;14) translocation.
• Prolymphocytic Leukaemia (PLL): More aggressive, larger cells with prominent nucleoli.
• Marginal Zone Lymphoma / Follicular Lymphoma: Different flow cytometry profiles (usually CD5 negative).
• Reactive Lymphocytosis: E.g., EBV/Glandular fever (viral infections cause polyclonal, not monoclonal, expansion).

📊 Staging (Binet System - UK/NICE Standard)

The Binet staging system is based on the number of involved lymphoid areas (neck, axillae, groins, liver, spleen) and the presence of cytopenias.

• Stage A: < 3 lymphoid areas enlarged. No anaemia or thrombocytopenia. (Normal life expectancy; usually no treatment needed).
• Stage B: ≥ 3 lymphoid areas enlarged. No anaemia or thrombocytopenia.
• Stage C: Anaemia (Hb < 100 g/L) and/or Thrombocytopenia (Platelets < 100 × 10&sup9;/L) regardless of lymph node involvement. (Requires treatment).

💊 Management (NICE Aligned)

• Watch and Wait: For asymptomatic early-stage disease (Binet A), treatment is not initiated. Early treatment does not improve survival and exposes patients to unnecessary toxicity.
• Indications for Treatment (IWCLL Criteria):
  • Progressive bone marrow failure (worsening anaemia/thrombocytopenia).
  • Massive (>10 cm) or progressive lymphadenopathy/splenomegaly.
  • Rapid lymphocyte doubling time (< 6 months).
  • Severe, refractory B-symptoms.
  • Autoimmune cytopenias unresponsive to steroids.
• Targeted Therapies (Modern Standard of Care): Chemoimmunotherapy (like FCR) is now rarely used. First-line therapies are chosen based on fitness and genetic markers (TP53/IGHV):
  • BTK Inhibitors: Acalabrutinib, Zanubrutinib, or Ibrutinib (continuous oral therapy).
  • BCL-2 Inhibitors: Venetoclax, often combined with an anti-CD20 monoclonal antibody like Obinutuzumab (fixed-duration therapy).
• Supportive Care:
  • Prompt antibiotics for infections.
  • Vaccinations (pneumococcal, annual influenza, COVID-19) – *Note: live vaccines should be avoided*.
  • IV Immunoglobulin (IVIG) replacement for severe, recurrent bacterial infections due to hypogammaglobulinaemia.
  • Corticosteroids for autoimmune complications (AIHA/ITP).

🧑‍⚕️ Case Examples - Chronic Lymphocytic Leukaemia (CLL)

• Case 1 (Incidental Lymphocytosis): A 72-year-old man has routine bloods for hypertension follow-up. FBC shows WCC 22 × 10&sup9;/L with predominant lymphocytosis, Hb 13.4 g/dL, platelets normal. He is well with no B symptoms. Flow cytometry demonstrates a clonal population of CD5+, CD23+ B cells. Diagnosis: Early-stage asymptomatic CLL (Binet Stage A). Management: "Watch and wait" with regular clinical and FBC monitoring.
• Case 2 (Symptomatic Progression): A 65-year-old woman presents with fatigue, drenching night sweats, and 5 kg weight loss. Examination reveals generalised lymphadenopathy and splenomegaly. Bloods: Hb 9.8 g/dL, WCC 65 × 10&sup9;/L, platelets 85 × 10&sup9;/L. Diagnosis: Symptomatic, advanced CLL (Binet Stage C) requiring treatment. Management: FISH testing for TP53/del(17p), followed by initiation of targeted therapy (e.g., Venetoclax + Obinutuzumab or a BTK inhibitor).
• Case 3 (Complication - Autoimmune Haemolysis): A 70-year-old man with known CLL presents with jaundice and dark urine. Hb 7.2 g/dL, reticulocytes high, LDH raised, direct Coombs test strongly positive for IgG. LFTs show unconjugated hyperbilirubinaemia. Diagnosis: Warm Autoimmune Haemolytic Anaemia (AIHA) secondary to CLL. Management: High-dose oral prednisolone. Folic acid supplementation. Monitor closely for response.

📋 References & NICE Guidelines

• NICE NG235: Haematological cancers: improving outcomes
• NICE TA687: Venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia
• NICE TA904: Zanubrutinib for treating chronic lymphocytic leukaemia
• BSH Guidelines: Management of Chronic Lymphocytic Leukaemia