Chronic Lymphocytic Leukaemia (CLL)

What is Chronic Lymphocytic Leukaemia?
Chronic Lymphocytic Leukaemia (CLL) is a type of cancer that affects lymphocytes, a type of white blood cell that plays a crucial role in the immune system. It is characterized by the slow and uncontrolled growth of abnormal B lymphocytes (a type of white blood cell) in the bone marrow, blood, and lymphoid tissues (such as lymph nodes and the spleen). CLL is the most common type of leukaemia in adults and tends to affect older individuals, with a median age at diagnosis of around 70 years.

Key Features of Chronic Lymphocytic Leukaemia
  • Chronic: Unlike acute forms of leukaemia, CLL typically progresses slowly over many years. The disease often grows insidiously and may not cause significant symptoms in its early stages.
  • Lymphocytic: Refers to the lymphocytes (specifically B cells) that are affected. These cells accumulate and crowd out normal blood cells, impairing the immune system.
  • Leukaemia: A cancer of the blood and bone marrow in which abnormal white blood cells proliferate uncontrollably.
Causes and Risk Factors

The exact cause of CLL is not fully understood, but several factors increase the risk of developing the disease:

  • Age: Most commonly diagnosed in people over 60 years; rare in younger individuals.
  • Gender: Men are more likely to develop CLL than women.
  • Family history: Increased risk if a first-degree relative has CLL.
  • Genetic mutations: Abnormalities such as deletions on chromosomes 13q, 11q, or 17p.
  • Environmental factors: Possible exposure to certain farming chemicals or radiation.
Pathophysiology of CLL

CLL arises from abnormal B lymphocytes that fail to undergo normal maturation and differentiation. These cells evade normal programmed cell death (apoptosis) and accumulate in the blood, bone marrow, and lymphatic tissues, overcrowding normal cells.

  • Increased abnormal lymphocytes: High numbers of small, mature-appearing but functionally incompetent lymphocytes.
  • Impaired immune system: Leads to infections and autoimmune complications where the immune system attacks healthy tissues.
Symptoms of CLL

Many people with CLL have no symptoms at diagnosis, and the disease is often discovered during routine blood tests. As the disease progresses, symptoms may include:

  • Enlarged lymph nodes (neck, underarms, or groin)
  • Enlarged spleen (splenomegaly) or liver (hepatomegaly)
  • Fatigue and weakness
  • Unexplained weight loss
  • Frequent infections
  • Night sweats
  • Easy bruising or bleeding due to low platelet counts

In some cases, CLL may evolve into a more aggressive lymphoma known as Richter’s transformation.

Diagnosis of CLL
  • Blood tests (CBC): High white blood cell count with increased lymphocytes.
  • Smudge cells: Fragile CLL cells seen on blood smear.
  • Flow cytometry: Confirms abnormal B-cell markers characteristic of CLL.
  • Bone marrow biopsy: Assesses marrow involvement.
  • Genetic testing: Identifies cytogenetic abnormalities such as del(13q), del(11q), del(17p), or TP53 mutations.
  • Immunophenotyping: Confirms the lymphocyte subtype involved.
Staging of CLL (Rai System)
  • Stage 0: Lymphocytosis only.
  • Stage I: Lymphocytosis with enlarged lymph nodes.
  • Stage II: Lymphocytosis with enlarged spleen and/or liver.
  • Stage III: Lymphocytosis with anaemia.
  • Stage IV: Lymphocytosis with low platelet count.
Treatment of CLL

Not all patients require immediate treatment. Many are managed with watchful waiting or active surveillance until symptoms or progression occur. When treatment is needed, options include:

  • Chemotherapy: Fludarabine, cyclophosphamide, or bendamustine.
  • Targeted therapies:
    • BTK inhibitors (ibrutinib, acalabrutinib)
    • BCL-2 inhibitors (venetoclax)
    • PI3K inhibitors (idelalisib, duvelisib)
  • Immunotherapy: Monoclonal antibodies (e.g., rituximab) and CAR T-cell therapy in relapsed cases.
  • Stem cell transplant: Considered in younger or treatment-resistant patients.
  • Radiation therapy: Occasionally used for bulky lymph nodes or spleen.
Prognosis
  • Early-stage CLL: Many patients live for years without treatment.
  • Advanced CLL: More aggressive disease, often requiring therapy.
  • Response to treatment: Newer targeted therapies (BTK and BCL-2 inhibitors) have significantly improved outcomes, even in relapsed disease.
Summary: Chronic Lymphocytic Leukaemia (CLL) is a slow-growing cancer caused by the accumulation of abnormal B lymphocytes in the blood, bone marrow, and lymphoid tissues. Many patients do not need immediate treatment, but effective chemotherapy, targeted therapies, and immunotherapy are available when required. Prognosis depends on disease stage, genetic mutations, and response to treatment.