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What is chronic myeloid leukaemia?

Chronic myeloid leukaemia (CML) is a cancer of white blood cells and is characterised by uncontrolled growth of the myeloid cells in the bone marrow.  This uncontrolled growth leads to myeloid cells crowding out the bone marrow, interfering with the production of normal blood cells (platelets, erythrocytes, neutrophils etc). In addition to crowding out the bone marrow, the abnormal myeloid cells spill into the peripheral blood. This is reflected in the full blood count which demonstrates abnormally raised levels of mature granulocytes (neutrophils, basophils and eosinophils).


Pathophysiology

CML was the first malignancy to be linked directly to a clear chromosomal abnormality. This abnormality involves a translocation between parts of chromosome 9 and 22, which leads to the formation of the so-called Philadelphia chromosome.  As a result, a gene contained on chromosome 22 called BCR fuses with a gene on chromosome 9 known as ABL. This creates a hybrid gene known as BCR-ABL.  This gene is able to add phosphates to tyrosine residues (a tyrosine kinase) and this allows BCR-ABL to activate a cascade of proteins which control the cell cycle, speeding up cell division.  In addition, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities.  These two actions of both speeding cell division and inhibiting DNA repair lead to chronic myeloid leukaemia.

Translocation leading to the BCR-ABL gene fusion

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Symptoms

Patients are often asymptomatic at diagnosis, presenting incidentally with an elevated white blood cell count on routine laboratory testing.

Symptoms of CML may include:

  • Upper abdominal pain – hepatosplenomegaly
  • Poor appetite – enlarged spleen may compress the stomach
  • Low-grade fever/night sweats – increased metabolism
  • Gout – increased cell turnover → excess purines → broken down to uric acid
  • Increased susceptibility to infections – ↓ functional immune cells
  • Shortness of breath/fatigue – anaemia
  • Easy bruising/petechiae/bleeding – low platelets
  • Neurological deficits/visual disturbance – hyperviscosity – leukocytosis

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Phases

The World Health Organisation (WHO) developed a set of criteria to define the various stages of CML. ¹

Chronic phase

Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. ² During this phase, patients are usually asymptomatic or have only mild symptoms of fatigue or abdominal fullness. The duration of the chronic phase is variable and without treatment, the disease will usually progress to the accelerated phase eventually (due to the accumulation of genetic mutations in addition to the BCR-ABL gene). ²

 

Accelerated phase

A patient is said to be in the accelerated phase when any of the following are present:

  • 10–19% myeloblasts in the blood or bone marrow
  • >20% basophils in the blood or bone marrow
  • Platelet count <100,000, unrelated to therapy
  • Platelet count >1,000,000, unresponsive to therapy
  • Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome
  • Increasing splenomegaly or white blood cell count, unresponsive to therapy

This phase is significant as it is a sign that the disease is progressing and that a blast crisis is imminent. ²

 

Blast crisis

Blast crisis is the final phase in the evolution of CML, and behaves like an acute leukaemia, with rapid progression and short survival. Blast crisis is diagnosed if any of the following are present in a patient with CML:

  • >20% myeloblasts or lymphoblasts in the blood or bone marrow
  • Large clusters of blasts in the bone marrow on biopsy
  • Development of a chloroma (a solid focus of leukaemia outside the bone marrow)

Diagnosis

Full blood count:

  • Leukocytosis
  • Increased numbers of eosinophils and basophils
  • Differential WCC shows granulocytes at all stages of development
  • Anaemia (normocytic/normochromic)

 

Biochemistry:

  • Lactate dehydrogenase is often raised
  • Urate may be raised (due to high cell turnover)
  • U&Es are usually normal at presentation

 

Peripheral blood film: 

  • All stages of granulocyte maturation noted
  • Appearances are similar to that of a bone marrow aspirate

 

Bone marrow aspirate:

  • Necessary to stage disease (% of blasts determines chronic vs accelerated vs blast crisis)
  • Allows cytogenetic sampling to confirm diagnosis – Philadelphia chromosome

 

The gold standard of diagnosis is the detection of the Philadelphia chromosome, which is present in 95% of people with CML. Methods for identifying the Philadelphia chromosome include:

  • FISH (fluorescent in-situ hybridisation)
  • PCR for the BCR-ABL gene

Management

Tyrosine Kinase Inhibitors (TKI)

Imatinib (1st generation TKI)

  • Imatinib targets BCR-ABL, blocking the ability of the gene to phosphorylate a tyrosine
  • It is better tolerated and more effective than previous therapies (due to its specificity)
  • This has revolutionised CML treatment
  • The 5-year survival for those treated with Imatinib is currently around 90%.
  • PCR testing of BCR-ABL transcript levels is used to monitor treatment response
  • The cost of Imatinib is high
  • Treatment is required for the rest of the patient’s life which could potentially be 20-30 years

 

Second generation TKI

  • A new generation of TKIs have followed Imatinib such as Nilotinib and Dasatinib
  • These drugs can now be used as first-line treatment, or as alternatives should resistance develop to another agent

 

Bone marrow transplantation

Bone marrow transplantation is a treatment option for those who do not respond well to drug treatments. This tends only to be used in younger, otherwise healthy patients. It does offer the possibility of a cure, however, there are a number of serious risks (including death), therefore the treatment is not suitable for many patients.


References

1. Vardiman J, Harris N, Brunning R (2002). “The World Health Organization (WHO) classification of the myeloid neoplasms”Blood 100 (7): 2292–302

2. Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era”. Hematology Am Soc Hematol Educ Program 2006: 240–5.


 

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