Chronic Lymphocytic Leukaemia (CLL) is the most common adult leukaemia in Western countries. It is a clonal disorder of mature B lymphocytes and has a highly variable clinical course, ranging from an indolent disease requiring no treatment to aggressive forms necessitating early intervention. This guide provides an overview of CLL for junior doctors rotating through haematology.

Understanding CLL

CLL is characterised by the accumulation of small, mature-looking but dysfunctional B lymphocytes in the blood, bone marrow, and lymphoid tissues. It is closely related to small lymphocytic lymphoma (SLL), with the distinction being that CLL primarily affects peripheral blood, whereas SLL involves lymphoid organs.

Clinical Presentation

CLL can be asymptomatic and detected incidentally on a routine full blood count. Symptomatic patients may present with:

• Lymphadenopathy – Most common initial presentation.
• Hepatosplenomegaly – Occurs in advanced disease.
• Recurrent infections – Due to immune dysfunction and hypogammaglobulinaemia.
• Fatigue & Weight Loss – B symptoms in more aggressive disease.
• Autoimmune Complications – Autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP).

Investigations

• Full Blood Count (FBC) & Blood Film – Lymphocytosis (>5 × 10⁹/L) with small mature lymphocytes and smear (smudge) cells.
• Flow Cytometry – Confirms clonal B-cell population with CD5, CD19, CD20 (dim), and CD23 positivity.
• Bone Marrow Aspirate & Biopsy – Not always required but shows increased lymphocytes.
• Cytogenetics & Molecular Testing – Prognostic markers:
  • FISH for del(13q), del(11q), del(17p) (p53 mutation – poor prognosis).
  • IGHV mutation status (mutated = better prognosis, unmutated = worse prognosis).
• Immunoglobulin Levels – Assesses hypogammaglobulinaemia.

Staging

Two staging systems guide prognosis and treatment decisions:

• Rai Staging (USA):
  • 0: Lymphocytosis only (low risk).
  • I-II: Lymphadenopathy and/or organomegaly (intermediate risk).
  • III-IV: Anaemia and/or thrombocytopenia (high risk).
• Binet Staging (Europe):
  • A: <3 lymphoid areas involved.
  • B: ≥3 lymphoid areas involved.
  • C: Anaemia and/or thrombocytopenia.

Management

Management depends on disease stage, symptoms, and genetic markers. Many patients do not require immediate treatment and are monitored under a watch and wait approach.

Supportive Care

• Infection Prevention – Vaccination (e.g., pneumococcal, influenza), IV immunoglobulin for recurrent infections.
• Autoimmune Cytopenias – Managed with steroids, rituximab, or immunosuppressants.
• Blood Transfusions – Symptomatic anaemia or thrombocytopenia.

Definitive Treatment

1. Indications for Treatment
   • Symptomatic disease (B symptoms, bulky lymphadenopathy, organomegaly).
   • Progressive marrow failure (anaemia or thrombocytopenia).
   • Rapid lymphocyte doubling time (<6 months).
   • Severe autoimmune complications unresponsive to steroids.
2. First-Line Therapy
   • Targeted Therapy (preferred):
     • Bruton’s tyrosine kinase (BTK) inhibitors: Ibrutinib, Acalabrutinib.
     • BCL-2 inhibitors: Venetoclax (often combined with anti-CD20 monoclonal antibodies like rituximab or obinutuzumab).
   • Chemoimmunotherapy (for selected fit patients with IGHV-mutated disease and no TP53 mutation):
     • FCR regimen (Fludarabine, Cyclophosphamide, Rituximab) – Younger patients.
     • Bendamustine + Rituximab – Older or frail patients.
     • Note this is (extremely) rarely used in the modern era
3. Relapsed/Refractory CLL
   • BTK inhibitors (Ibrutinib, Acalabrutinib) or BCL-2 inhibitors (Venetoclax) if not used first-line.
   • PI3K inhibitors (e.g., Idelalisib) in selected cases.
   • Allogeneic stem cell transplantation for high-risk, refractory disease.

Palliative Care

• For elderly or frail patients with slow disease progression, best supportive care is often appropriate.
• Symptom management with transfusions, steroids for autoimmune cytopenias, and infection prophylaxis.
• Clear goals-of-care discussions, particularly in advanced disease.

Complications to Watch For

• Infections – Bacterial, viral (zoster), and fungal due to immunosuppression.
• Tumour Lysis Syndrome (TLS) – Need to assess TLS risk and institute management as required when starting venetoclax.
• Richter’s Transformation – Transformation to an aggressive lymphoma (diffuse large B-cell lymphoma); suspect in rapidly enlarging lymph nodes or new B symptoms.
• Autoimmune Cytopenias – Haemolytic anaemia or thrombocytopenia.
• Secondary Malignancies – Increased risk due to immune dysfunction and prior treatments.

Prognosis and Follow-Up

• Indolent cases may never require treatment and have a normal life expectancy.
• Patients with TP53 mutations, del(17p), or unmutated IGHV have a poorer prognosis and require novel targeted therapies.
• Regular follow-up includes monitoring blood counts, lymphadenopathy, and signs of transformation or progression.

Key Takeaways for Junior Doctors

1. CLL is often asymptomatic and detected incidentally.
2. Flow cytometry confirms the diagnosis by demonstrating a clonal B-cell population.
3. Many patients follow a watch and wait approach, with treatment initiated only when clinically necessary.
4. Targeted therapies (BTK and BCL-2 inhibitors) have replaced chemotherapy for most patients.
5. Recognising Richter’s transformation and autoimmune complications is crucial for prompt intervention.
6. Palliative care should be considered for frail patients with advanced disease.

CLL is a fascinating and heterogenous disease with a rapidly evolving treatment landscape. Junior doctors play an essential role in recognising its presentation, monitoring progression, and initiating appropriate management.

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