CML is a myeloproliferative disorder - a myeloproliferative disorder is characterised as a disease of the bone marrow in which excess cells are produced.
CML definition: a malignant clonal proliferation of pluripotent haemopoietic stem cells (blood stem cells). It has the ability to affect more than one cell line.
CML affects around 1-2 people out as a population of 100,000, thus around 0.00001%, and has a slightly higher rate in males. It can occur at any age range, however it is more likely in the middle-aged to elderly age range. CML makes up around 14% leukaemias occurring in adults. There are around 700 diagnosed cases per year within the United Kingdom.
The cause of CML isn't very well researched, thus little is known about it. One theory is the exposure to ionising radiation, such as that present within Hiroshima after World War 2. CML does however have a link to a clear genetic abnormality, in fact it was the first malignancy to be related to this.
The BCR gene located on chromosome 22 becomes fused with the ABL gene located on chromosome 9, created a BCR-ABL fusion gene, which when translated into a protein formed tyrosine kinase. This fusion gene is found in roughly 90% of all CML cases. The translocation of the genes results in one of the chromosome 9s becoming longer, and one of the chromosome 22s becoming shorter. The chromosome 22 is referred to as the Philadelphia chromosome.
The Ph gene is also located in adults and children with ALL (25-30% and 2-10% respectively).
Ph gene: T(9;22)(q34:q11).
A patient with CML can be asymptomatic, however the symptoms (when they do occur) come in the form of:
- Splenomegaly (enlargement of the spleen)
- Hepatomegaly (enlargement of the liver)
- Malaise
- Bruising
- Bleeding
- Anaemia
- Reduced platelet count
CML can be categorised into 3 stages:
- Chronic phase: May last for a prolonged amount of time, typical CML, 85% of patients are usually in this phase. Usually asymptomatic, or mild symptoms such as fatigue, abdominal fullness etc. How long this will last will depend on how early the diagnosis was made, without curative treatment, it will progress.
- Accelerated phase: In this phase there is approximately 10-19% of myeloblasts in the blood/marrow, and over 20% of basophils located in the blood or marrow. Platelet count can be less than 100,000 or over 1,000,000. Other genetic abnormalities occur alongside to the Ph chromosome. White blood cell count with increase and splenomegaly will increase. May be unresponsive to therapy.
- Blast crisis: Terminal phase, behaves clinically like acute leukaemia, over 20% of myeloblasts are found within the blood/marrow. There are also large clusters of blasts in the marrow. A chloroma will form, this is a solid focus of leukaemia outside of the marrow. This is also found in AML, and this can transform into megakaryocytic (the cell in which platelets originate from) leukaemia.
Iminitab was one of the first drugs designed around the molecular biology of CML, it is an inhibitor of the protein formed from the Ph (BCR-ABL) gene, it also inhibits proliferation and induces the action of apoptosis in cells which are positive for the BCR/ABL gene, and also Ph+ leukaemic clones. The iminitab molecule fits into the active sid e of the ABL protein, disallowing the binding of ATP, meaning the ABL protein cannot phosphorylate its substrates. Around 90% of patients treated with this drug showed slowed or no further disease progression.
