Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Sprycel (Bristol-Myers Squibb)
20 mg, 50 mg and 70 mg tablets
Approved indication: chronic myeloid leukaemia and acute lymphoblastic leukaemia
Australian Medicines Handbook section 14.3.5
Most patients with chronic myeloid leukaemia have a chromosomal translocation that produces the Philadelphia chromosome (Ph). This results in an abnormal tyrosine kinase which causes cells to become malignant. This translocation can also occur in patients with acute lymphoblastic leukaemia.
Imatinib (see New drugs, Aust Prescr 2001;24:129-31) is an inhibitor of this abnormal tyrosine kinase and is effective in many patients with newly diagnosed chronic myeloid leukaemia. However, some patients are resistant to imatinib when they start therapy or develop resistance during therapy due to mutations in the abnormal tyrosine kinase gene. These mutations interfere with imatinib binding.
Dasatinib is a new tyrosine kinase inhibitor that binds to a broader range of kinases compared to imatinib. In vitro, dasatinib has been shown to have inhibitory activity against imatinib-resistant leukaemia cell lines.
After oral administration of dasatinib, maximum plasma concentrations are observed within 0.5-3 hours and it has an overall mean terminal half-life of 5-6 hours. Dasatinib is extensively metabolised, mainly by cytochrome P450 3A4, and is predominantly eliminated in the faeces as metabolites.
Other drugs that inhibit cytochrome P450 3A4, such as erythromycin and other macrolides, may increase exposure to dasatinib and should be avoided. Likewise, inducers of cytochrome P450 3A4, such as dexamethasone, rifampicin, carbamazepine and St John's wort may reduce the concentrations of dasatinib and are not recommended. Dasatinib increases the risk of toxicity from other cytochrome P450 3A4 substrates that have a narrow therapeutic index, such as quinidine and ergot alkaloids. H2blockers and proton pump inhibitors are likely to reduce the oral bioavailability of dasatinib and are not recommended. If antacids are used, they should be given two hours before or after taking dasatinib.
The efficacy of dasatinib was first assessed in a phase I dose-escalation study in 84 patients with chronic myeloid leukaemia or Ph-positive acute lymphoblastic leukaemia who could not tolerate or were resistant to imatinib. Patients received 15-240 mg of dasatinib orally per day. Following treatment, 68 (81%) patients had a major haematological response (assessed by counting white blood cells, platelets, blasts and myelocytes and metamyelocytes in peripheral blood), and 37 (44%) patients had a major cytogenetic response (based on the percentage of Ph-positive cells in metaphase in bone marrow). Responses were maintained in 95% of patients with chronic-phase disease (median follow-up of 12 months) and 82% of patients with accelerated disease (median follow-up of 5 months). Most patients with lymphoid blast crisis or Ph-positive acute lymphoblastic leukaemia relapsed within six months.1
An open-label phase II trial studied the efficacy of dasatinib (70 mg taken twice a day) in 186 patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukaemia. After eight months, 168 (90%) patients achieved complete haematologic responses and 97 (52%) achieved major cytogenetic responses. Sixteen patients developed progressive disease or died.2
Another study assessed the efficacy of dasatinib (70 mg taken twice a day) from combined data of open-label phase II trials in patients (resistant or intolerant to imatinib) with chronic myeloid leukaemia in blast crisis. Of these patients, 74 had myeloid blast crisis and 42 had lymphoid blast crisis. After 8 months, dasatinib had induced major haematologic responses in 31-34% of patients. Major cytogenetic responses were observed in 31% of patients with myeloid blast crisis and 50% of patients with lymphoid blast crisis.3
In the phase II trials, response rates to dasatinib were similar in patients with imatanib-resistant tyrosine kinase mutations compared to patients without mutations. However, one particular mutation (T3151) conferred resistance to both dasatinib and imatinib treatment in the phase I and II trials.123
Myelosuppression was a common adverse effect of dasatinib treatment. In the phase I trial of 84 patients, about 60% of them had their treatment interrupted because of myelosuppression and 25% had their dose reduced. Other common adverse events included pleural effusions (18% patients), diarrhoea (23% patients), peripheral oedema (19% patients), nausea (10% patients), dyspnoea or pulmonary oedema (12%), rash (11%), headache (10%) and gastrointestinal haemorrhage (8%).1These adverse events were also common in the phase II trials. 23There have been reports of intracranial haemorrhage, which have been fatal in some patients.
As myelosuppression is common with dasatinib treatment, patients should have regular complete blood counts. Dasatinib should be administered with caution in patients who have or are likely to develop a prolonged QTc interval.
Dasatinib provides a second-line treatment for patients with imatinib-resistant chronic myeloid leukaemia or Ph-positive acute lymphoblastic leukaemia. However, resistance to dasatinib has been observed in some patients. The effect of this drug on long-term patient survival is unknown.
- Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531-41.
- Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109:2303-9.
- Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. Epub 2006 Dec.