50 mg and 100 mg capsules
Approved indication: chronic myeloid leukaemia
Australian Medicines Handbook Section 14.3.9
Most patients with chronic myeloid leukaemia have a translocation of chromosomes9 and 22. The abnormal chromosome, known as the Philadelphia chromosome, resultsin the production of an abnormal tyrosine kinase. This enzyme contributes to the production of malignant cells.
Imatinib aims to inhibit the abnormal tyrosine kinase. This action stops cell proliferation and can induce apoptosis of tumour cells.
The drug is well absorbed so it can be given by mouth. It has a half-life of 18 hours and is mainly cleared by metabolism. This metabolism involves cytochromeP450 3A4 so there is a potential for interactions with inhibitors of this enzyme such as grapefruit juice, erythromycin and ketoconazole. Although there have been no studies, drugs such as phenytoin, carbamazepine, dexamethasone and St John's wort may reduce the concentrations of imatinib by inducing P450 3A4.Imatinib has other potential interactions because it also inhibits P450 2D6and 2C9.
In a pilot study 58 patients with chronic myeloid leukemia who were in blast crisis, were treated with daily doses between 300 mg and 1 g. There was a response in 14 of the 20 patients with a lymphoid blast crisis or acute lymphoblastic leukaemia. In the 38 patients with myeloid blast crisis 21 responded.1
Another study treated 83 patients with chronic myeloid leukaemia who had not responded to interferon alfa. All the patients who took 140 mg or more had at least a 50% fall in their white blood cell count.2
These early trials were followed by larger studies. In a study of 532 people with chronic myeloid leukaemia who had been unsuccessfully treated with interferon there was a complete haematological response in 88% of the patients. (Their white cell counts fell below 10 x 109/L.) In 15% of patients there was a confirmed cytogenetic response as bone marrow biopsy showed no cells with the Philadelphia chromosome. A study of 235 patients in the accelerated phase of the disease showed that 400 mg or 600 mg imatinib produced a complete haematological response in 28% and a confirmed complete cytogenic response in 4%. In patients with myeloid blast crisis there was a complete haematological response in 4% and a confirmed complete cytogenic response in 1%.
During clinical trials up to 68% of patients reported nausea and many vomited. Fluid retention occurred in up to 68% but could often be managed with diuretics. Regular blood counts are required as imatinib is associated with anaemia, neutropenia and thrombocytopenia. Haemorrhage occurred in 13% of the patients who failed interferon therapy and in 48% of those with a myeloid blast crisis. Particular caution is needed if the patient is also taking warfarin. One patient died of acute liver failure which could have been related to an interaction with paracetamol. High doses of paracetamol should therefore be avoided.
Most patients have been followed up for less than six months so there are no long-term safety data about imatinib. There is also a possibility that drug resistance could develop. Further research is needed as it is not yet known whether or not the improvements in laboratory results will lead to better clinical outcomes for the patients.
- Sawyers CL, Reese SF. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038-42. .
- Peng B, Buchdunger E, Resta DJ. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-7. .