Chronic Myeloid Leukaemia (CML)

Key Features of Chronic Myeloid Leukaemia

• Chronic: Unlike acute leukaemia, which develops rapidly, CML is a slow progressing disease and may develop over several months or even years before symptoms become noticeable.
• Myeloid: Refers to the type of white blood cells involved in the disease, specifically granulocytes (such as neutrophils, eosinophils, and basophils), which are part of the body’s immune system.
• Leukaemia: Refers to cancer of the blood, where there is an uncontrolled growth of white blood cells.

The Genetic Basis of CML

The hallmark of CML is the presence of a specific genetic abnormality called the Philadelphia chromosome. This abnormality occurs when chromosome 9 and chromosome 22 break and swap parts, creating a new abnormal gene called BCR-ABL. The BCR-ABL fusion gene encodes a protein that acts like a “fuel” for the uncontrolled growth of myeloid cells. This protein is a tyrosine kinase that promotes excessive cell division and blocks normal cell death.

• Philadelphia chromosome: Found in more than 95% of CML cases and is a key diagnostic marker for the disease.

Phases of CML

CML progresses in three phases:

• Chronic phase: Early phase with mild or no symptoms. White blood cell levels are relatively controlled and this phase may last for years.
• Accelerated phase: Disease becomes more aggressive, with increasing blasts, worsening symptoms, and reduced response to treatment.
• Blast crisis: The most severe phase, behaving like acute leukaemia, with a dramatic increase in blasts, severe symptoms, and poor prognosis without aggressive treatment.

Symptoms of CML

In early stages, CML may have few or mild symptoms and is often detected during routine blood tests. Common symptoms include:

• Fatigue or feeling weak
• Unexplained weight loss
• Night sweats
• Fever
• Pain or a feeling of fullness below the ribs (enlarged spleen or liver)
• Paleness due to anaemia
• Easy bruising or bleeding due to low platelet counts
• Frequent infections due to impaired white blood cell function

Symptoms become more severe as the disease progresses into the accelerated or blast phase.

Diagnosis of CML

• Blood tests: Full blood count shows very high white blood cell levels with immature cells; basophils and eosinophils may be increased.
• Bone marrow biopsy: Confirms diagnosis and determines disease phase.
• Genetic testing: Detection of the Philadelphia chromosome or BCR-ABL gene using FISH or PCR testing on blood or bone marrow.

Treatment of CML

Treatment of CML has been transformed by targeted therapies that specifically inhibit the BCR-ABL protein.

• Tyrosine kinase inhibitors (TKIs): Imatinib was the first TKI and revolutionised treatment. Other TKIs such as dasatinib, nilotinib, and bosutinib are used when resistance or intolerance occurs.
• Stem cell transplant: Considered for patients who do not respond to TKIs or who enter blast crisis; potentially curative but high risk.
• Chemotherapy: Mainly used in blast crisis or when resistance to TKIs develops.
• Supportive care: Blood transfusions, antibiotics, symptom management; rarely, splenectomy may be considered.

Prognosis

• Chronic phase: With TKIs, most patients live normal or near-normal lifespans with remission rates over 90%.
• Accelerated phase: Harder to control; stem cell transplant may be considered.
• Blast crisis: Poor prognosis without aggressive treatment such as chemotherapy and transplant.

Resistance to TKIs or mutations in the BCR-ABL gene may develop over time, but newer TKIs and alternative treatments offer options for managing resistant disease.