Chronic myeloid leukaemia (CML)

Definition
CML is due to a clonal proliferation of a mature hemopoietic stem cell in the myeloid series. This
cell retains some degree of differentiation.

almost exclusively a disease of adults

Peak of presentation being between 40 and 60 years

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Pathogenesis
The pathogenesis is genetic in origin. In most patients (> 90%) there is a balanced translocation
between chromosome 9 and 22, bringing the c-ABL gene in close proximity with BCR gene on
chromosome 22. This causes formation of a new gene which is known as BCR-ABL1. This gene
causes increased activity of an enzyme known as tyrosine kinase and subsequent elevation in
the rates of cell proliferation in the myeloid series.
The new chromosome created by the translocation is referred to as the Philadelphia
chromosome.

Clinical manifestations

Unlike the acute leukaemias, which are either rapidly reversed or rapidly fatal, CML has a more
slowly progressive course through three distinct phases:
- chronic phase
- accelerated phase
- blast crisis

If left untreated, the disease will evolve through these phases and ultimately transform to acute
leukaemia (blast crisis – 75% myeloid, 25% lymphoid) or myelofibrosis, with death in a median of
3–4 years.
Fortunately, targeted therapy to arrest disease progression is highly effective in the majority of
patients.

Most patients present in the indolent/chronic phase.

In the chronic phase the patients may present with anemia and constitutional symptoms.
The accelerated phase and blast transformation phase present in similar fashion to an acute
leukaemia, with marrow failure, leukostasis and organ infiltration.
 • symptomatic anaemia (e.g. shortness of breath)
• abdominal discomfort due to splenomegaly
• Constitutional symptoms- weight loss, fever and sweats in the absence of infection
• headache (occasionally) or priapism due to hyperleucocytosis
• bruising and bleeding (uncommon).
• Leucostasis – more common in blast transformation

Signs
• pallor
• splenomegaly, often massive – commonest finding – corresponds with the tumor burden
• lymphadenopathy (uncommon; suggests blast crisis)
• extramedullary soft tissue leukaemic deposit – ‘chloroma’ (indicates blast crisis)
• retinal haemorrhage due to leucostasis.

Investigations

Investigations to confirm the diagnosis

FBC
● High WBC counts
● Prominent cells are neutrophils with left shift – with prominence of band
forms, myelocytes, metamyelocytes and a few blasts
● Basophils and eosinophils are also increased
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● Thrombocytosis

Marrow examination
● Hypercellular marrow with high myeloid to erythroid ratio
● Blast cells are present, but usually less than 5%. (Higher blast cell percentage
of >15% may indicate blast crisis)
Cytogenetics
● Demonstration of the Philadelphia chromosome
● Ph chromosome negative patients have a poor prognosis compared to Ph
positive patients.

Treatment

Supportive treatment should be offered to all patients based on the disease manifestations and
associated complications.

General management
The patient should be informed of the diagnosis emphasizing the fact that highly effective
treatment is available.

Definitive treatment

▪ As mentioned above, the enzyme tyrosine kinase is central to the pathogenesis of CML.
Therefore, medication targeting this pathway is now widely used in the management.
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Tyrosine kinase inhibitors such as imatinib are highly effective in the treatment of CML and
patients can have close to normal survival rates.

Treatment response is monitored by the cytogenetic response, with Ph chromosome in

peripheral blood.

Tyrosine kinase inhibitors are available in Sri Lanka and patients should be referred to an
oncologist or clinical haematologist for further management.

▪ Bone marrow transplantation is also an accepted modality of management in these patients,

usually with failure of TK inhibitor therapy
It is also indicated in patients with accelerated disease/blast crisis.
Bone marrow transplantation for CML is currently not available in Sri Lanka.