Pre Clinical Biology

Myeloid cells are any white blood cell type that is not lymphoid. However, in Chronic Myeloid Leukaemia (CML) the cell type diving abnormally is most often a blast cell of the neutrophil lineage. Unopposed, CML exists in three stages as determined by the amount of blasts: Chronic (<20% blasts) is the phase most patients present in. It can last roughly 4 years if untreated and is symptomatically quiet. Accelerated, this phase is characterised by worsening symptoms such as fatigue, buising, weight loss, night sweats and splenomegaly. Blastic (>20% blasts) is now a phase rarely encountered in clinical practice, it is characterised by the CML transforming into an acute leukaemia. Usually this acute transformation is to acute myeloid leukaemia but 20% of cases turn into acute lymphoid leukaemia.

CML is a relatively rare cancer, existing more in men than women and accounting for 15% of leukaemias. It has no clear risk factors other than radiation exposure.

Philadelphia Chromosome (Ph)

This important cytogenetic aberration is specific to CML. The vast majority of cases have Ph positive leukaemic cells when analysed using karyotyping. Its specificity to CML has also meant that it is a useful pharmacological target for chemotherapy. By targeting the product of this specific genetic abnormality, the cancer cells and not normal rapidly dividing cells are targeted. This achieves an effective cell kill with minimal damage to normal cells.

Ph is chromosome 22 after a portion of chromosome 9 has been swapped with a portion of chromosome 22 in a reciprocal translocation. This creates the BCR-ABL fusion gene, which codes for the BCR-ABL tyrosine kinase. This molecule enables indefinate growth through consistant activation of the downstream signal transduction pathway.

The translocation responsible for Ph. Taken from http://www.cmlsociety.org/?q=node/14

Clinical Features

In the history you may find the patient to have symptoms of hypermetabolism (lethargy, night sweats) owing to the high numbers of white cells. Platelet function is abnormal in CML, so symptoms of easy brusing, menorrhagia and particularly mucosal bleeding may be present.

Rarely, the patient may present with symptoms of leucostasis. This is a condition in which the high cell load of the bloodstream results in a high viscosity of the blood. As a result, the blood stagnates in microcirculation and can cause priapism, visual disturbances and headaches.

An important point to remember is that approximately a third of patients are diagnosed with CML despite having no specific symptoms and are alerted to haematology after a full blood count ordered for a different reason shows a high white cell count.

On examination, 75% of patients will be found to have splenomegaly. This is usually massive, as the spleen can be felt more than five finger widths from the costal margin. Such a large spleen may cause discomfort when eating. Remember that to examine the spleen you should palpate from the right iliac fossa towards the left hypochondrium as this is the direction the spleen enlarges in. This is so that you do not miss a very large spleen, the kind you might find in CML.

Lymphadenopathy is rare as the cells involved in CML are myeloid so do not circulate in the lymphatics. 

Investigations

Initial investigations should include a full blood count and blood film. This will show neutrophilia (usually 100-300x10e9/L is the total white cell count), normochromic normocytic anaemia and normal or raised platelets. Abnormal blasts may be visible in the peripheral blood film, however these require specialist interpretation and molecular studies carry more diagnostic weight.

Lactate dehydrogenase (LDH) is an intracellular enzyme that will be raised in CML owing the the high numbers of cells being produced and dying. Urate is also raised for this same reason as it is an intracellular molecule.

Erythrocyte sedimentation rate will be raised as well, though this is a non specific investigation.

Specialist investigations that are used to diagnose CML involve taking a bone marrow aspirate and examining morphology. This will show a hypercellular marrow with less than 20% abnormal blasts to qualify as a chronic leukaemia. Most importantly, cytogenetic studies will reveal the Philadelphia chromosome. Sometimes when the chromosome is not visible (~5% of cases), polymerase chain reaction studies of the BCR-ABL fusion gene can be used.

Treatment

The first line treatment for CML is Imatinib (trade name Gleevec). This drug works by binding to the BCR-ABL protein and blocking its activity. As it targets this molecule specifically, there is a targeted and effective response against the leukaemic cells. As a result of this, the side effect profile is minimal and mild (e.g. nausea, oedema).

Allopurinol is given alongside Imatinib to prevent hyperuricaemia, which can occur because of the rapid cell kill. This occurs as part of the 'tumour lysis syndrome', characterised by hyperphosphataemia, hypocalcaemia, hyperkalaemia and hyperuricaemia in response to powerful chemotherapy.

Imatinib is a highly effective drug with a 89% 5yr survival rate. However, some patients fail to respond to Imatinib, if the patient is eligible bone marrow transplantation is often used. This is potentially curative but carries a 20% risk of mortality.

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