Around a fifth of all leukaemias are the chronic myeloid form (CML), but not all patients respond to imatinib and others develop resistance to the drug
There are numerous forms of leukaemia, all of which are characterised by an overproduction of abnormal or immature white blood cells. The resultant suppression in the production of normal white cells, red blood cells and platelets leads to a collection of knock-on effects, including anaemia, thrombocytopoenia and neutropoenia.
Around a fifth of all leukaemias are the chronic myeloid form (CML), caused by a proliferation of those cells that are produced in the bone marrow’s myeloid areas. The chronic phase typically lasts for about five years, followed by another year of accelerated phase. Finally, the blastic stage involves very severe symptoms, and a life expectancy of between three and six months.
While the outlook for patients with CML improved dramatically in 2001 with the introduction of Novartis’s imatinib (Glivec), a tyrosine kinase inhibitor active in patients positive for the Philadelphia chromosome, not all patients respond, and others develop resistance to the drug. As a result, several follow-on compounds have been developed, including Pfizer’s bosutinib.1
Like imatinib, it inhibits the Bcr-Abl tyrosine kinase, thus stopping the downstream signalling cascade it initiates. In a Phase I/II trial, 288 patients with chronic phase imatinib-resistant or -intolerant CML, and no other prior kinase inhibitor exposure, were given 500mg doses of the drug once a day.2 After 24 weeks, 31% of the patients had achieved a major cytogenetic response, and after a median follow-up of two years, 86% had achieved complete haematologic remission, with 53% having had a major cytogenetic response and 41% a complete cytogenetic response. The progression-free survival rate at two years was 92%. The most common adverse event was mild to moderate diarrhoea.
In another Phase I/II study, the treatment group included 118 patients with chronic phase CML who had failed on one or both of two other kinase inhibitors, nilotinib and dasatinib, as second line therapy after failure on imatinib.3 A third of the subjects experienced a major cytogenetic response, and a quarter a complete cytogenetic response, including one patient who had received all three alternative drugs previously. After two years, the progression-free survival was 73%.
In a Phase III clinical trial comparing bosutinib with imatinib in newly diagnosed chronic phase CML patients, 502 subjects were given 500mg bosutinib or 400mg imatinib once a day.4 The complete cytogenetic response rate was very similar with both drugs – 70% for bosutinib and 68% for imatinib – and although the major molecular response rate at one year was higher with bosutinib, and both this and the cytogenetic response rate were achieved more quickly than in the imatinib group, it did not meet the primary endpoint for complete cytogenic response at 12 months.
The drug has now been given conditional approval by EMA for patients who are resistant or intolerant to prior therapies. It is also being evaluated in solid tumours, including breast cancer, in which a Phase II trial has been carried out.5
A total of 73 patients with locally advanced or metastatic breast cancer who had already received chemotherapy were given 400mg oral daily doses of single-agent bosutinib. The two-year overall survival rate was 26%, with the main adverse events diarrhoea, nausea and vomiting. Trials continue.
1. M. Puttini et al. Cancer Res. 2006, 66, 11314
2. J.E. Cortes et al. Blood, 2011, 118, 4567
3. H.J. Khoury et al. Blood, 2012, 119, 3403
4. J.E. Cortes et al. J. Clin. Oncol. 2012, 30, 3486
5. M. Campone et al. Ann. Oncol. 2012, 23, 610