3 The technology
3.1 Imatinib (Glivec) is the first in a new class of cancer drugs, the signal-transduction inhibitors, rationally designed to competitively inhibit BCR-ABL tyrosine kinase activity. By blocking specific signals in cells expressing the BCR-ABL protein, imatinib reduces the uncontrolled proliferation of white blood cells that is a characteristic feature of the disease.
3.2 Imatinib initially received marketing authorisation from the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of people with Philadelphia-chromosome-positive CML in the chronic phase after failure of IFN-α, or in the accelerated phase or blast crisis, despite the absence of evidence from randomised controlled trials (RCTs); this was in November 2001. The licence was granted "under exceptional circumstances" and on the basis of the data on surrogate measures such as overall haematological and cytogenetic response rates, and progression-free survival. The EMEA stated that "the indications for which the medicinal product in question [imatinib] is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence/data on the quality, safety and efficacy of the medicinal product". Recently, the licence was extended, on the basis of new evidence from an RCT, to include the treatment of people with newly diagnosed Philadelphia-chromosome (bcr-abl)-positive CML for whom SCT is not considered as the first line of treatment.
3.3 The manufacturer's Summary of Product Characteristics (SmPC) states that there are no controlled trials demonstrating an increase in survival. It also states that the effect of imatinib on the outcome of SCT has not been determined, and that the experience with imatinib in children with CML is very limited.
3.4 The majority of people taking imatinib experience adverse reactions at some stage. The most frequently reported adverse effects of imatinib in clinical studies include nausea, vomiting, oedema (fluid retention), muscle cramps, skin rash, diarrhoea, abdominal pain, headache and fatigue. Cytopenia, particularly neutropenia and thrombocytopenia, has been reported in all studies, with a higher incidence in people in blast crisis and in the accelerated phase compared with those in the chronic phase. In clinical studies, 1% of people in the chronic phase, 2% of those in the accelerated phase, and 5% of those in the blast-crisis phase were withdrawn because of adverse events. For full details of side effects and contraindications, see the SmPC.
3.5 The recommended dosages of imatinib in the SmPC are400 mg/day in the chronic phase and 600 mg/day in the accelerated phase and blast crisis. The dose is taken orally, once daily, with a meal and a large glass of water. Dose escalation from 400 mg/day to 600 mg/day for people in the chronic phase, and from 600 mg/day to 800 mg/day (given as 400 mg twice daily) for people in the accelerated phase or blast-crisis phase is sometimes considered, provided that there is no severe adverse drug reaction or severe nonleukaemia-related neutropenia or thrombocytopenia.
3.6 Imatinib costs £12.98/100 mg (excluding VAT; British National Formulary 45, March 2003). The approximate annual cost of imatinib is between £19,000 and £28,500 for a person in the chronic phase, and between £28,500 and £38,000 for a person in the accelerated phase or in blast crisis, depending on the dose.