Chronic myeloid leukaemia – imatinib
Leukaemia is a collection of malignant diseases, in which overproduction of immature or abnormal white blood cells leads to suppressed production of normal white cells, plus red blood cells and platelets. This results in a variety of conditions, such as anaemia, neutropenia and thrombocytopenia.
Chronic myeloid leukaemia (CML) results from a proliferation of the cells formed in the myeloid areas of the bone marrow. The disease begins with a chronic phase and progresses through an accelerated phase to the final blastic stage where the symptoms can be severe, and life expectancy is only three to six months.
Chemotherapy can control the disease in the chronic phase, but although it can improve the symptoms, it has no effect on disease progression. The only cure is allogeneic stem cell transplantation, but there is a lack of a suitable donor.
The disease is a result of deregulated tyrosine kinases, so a signal transduction inhibitor that acts on tyrosine kinase could be the answer. Such a compound has been developed by Novartis, initially coded as CGP-57481, then STI-571, and now referred to as imatinib mesilate1. It binds with the ATP binding site of tyrosine kinase, acting on the Philadelphia chromosome that is abnormal in most CML patients.
In a multicentre open-label Phase II clinical trial, hundreds of patients suffering from chronic myeloid leukaemia or acute lymphoid leukaemia were initially given 400mg of the drug once a day, and then 600mg. Good haemotological responses were seen in up to 78% of the patients involved, one study saw 56% of patients having excellent cytogenetic responses, while in another, 71% had their bone marrow cellularity reduced to normal or less2.
In a further trial in 47 newly diagnosed CML patients, 77% achieved complete or major cytogenetic responses, and all bar one had normalised blood counts for at least four weeks3.
The drug could also have potential as a treatment for any form of tumour that is either caused by or dependent on these tyrosine kinases.