Proliferation of myeloid cells - granulocytes and their precursors, other lineages (platelets)

Aetiology

• The cytogenetic change that is characteristic of CML is the Philadelphia chromosome, which is a translocation of genes between chromosome 9 and 22: it is a t(9:22) translocation
  • Results in a new gene - BCR-ABL1
  • The gene product is a tyrosine kinase which cause abnormal phosphorylation leading to the haematological changes in CML

Pathophysiology

Three typical phases, the chronic phase, the accelerated phase and the blast phase:

• The chronic phase can last around 5 years, is often asymptomatic and patients are diagnosed incidentally with a raised white cell count
• The accelerated phase occurs where the abnormal blast cells take up a high proportion of the cells in the bone marrow and blood (10-20%)
  • In the accelerated phase patients become more symptomatic, develop anaemia and thrombocytopenia and become immunocompromised
• The blast phase follows the accelerated phase and involves an even high proportion of blast cells (>30%)
  • This phase has severe symptoms and pancytopenia
  • It is often fatal

Clinical features

• Asymptomatic
• Splenomegaly
• Hypermetabolic symptoms
• Gout - caused by high cell turnover rate giving a high urate
• Other: problems related to hyperleucocytosis, priapism

Investigations

• Bloods:
  • FBC: normal or decreased Hb, ↑ WBC, platelets low, normal or raised
    • Exclude other causes of raised granulocytes e.g. infection, post-surgery, steroids
  • Blood film: neutrophilia, i.e. abnormally high number of neutrophils, with myeloid precursors including blasts
  • Leukocyte alkaline phosphatase (LAP) - ****usually reduced
• Bone marrow biopsy:
  • Not generally required for diagnosis but would show increased cellularity with increased granulocytes etc.
  • FISH used to look for the cytogenic abnormality, cytogenetics will show Philadelphia chromosome in 97% of cases (can be tested in blood or bone marrow)

Management

• Fatal without stem cell/bone marrow transplant in the chronic phase
• Durable treatment responses with tyrosine kinase inhibitors e.g. imatinib
  • Prevents the action of the BCR-ABL fusion protein i.e.this is the abnormal protein produced by the Ph mutation