The Pharmaceutical Journal
Vol 279 No 7482 p673
15 December 2007

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New alternatives to imatinib emerge for CML patients

Positive results for a wave of new treatments for chronic myeloid leukaemia patients who do not respond to imatinib therapy were presented at the annual meeting of the American Society of Hematology in Atlanta, Georgia, this week.

The potential of these new drugs is also discussed in a Lancet Oncology paper (2007;8:1116). The paper points out that, although the first-generation tyrosine-kinase inhibitor imatinib can induce excellent long-term responses in most patients, around a quarter of patients will not respond or will lose previous responses and for these patients other treatment options are needed.

Loss of response to imatinib is most commonly associated with selection for a limited number of BCR-ABL kinase domain mutations that impair the ability of imatinib to effectively bind to BCR-ABL.

Data from trials of drugs that bind 20–200 times more effectively to BCR-ABL than imatinib were presented at the ASH meeting.

Nilotinib is 20–30 times more potent than imatinib at binding to BCR-ABL domains. The results of a trial involving 320 patients intolerant or resistant to imatinib showed that 76.2 per cent of patients who had not yet achieved haematological remission did so within one month of starting treatment. Researchers also found that, although nilotinib and imatinib have some molecular similarities, intolerance to both is rare.

Bosutinib is 200 times more potent than imatinib at binding to BCR-ABL domains. Preliminary data from 98 patients showed that bosutinib therapy led to complete haematological responses in 17 of 23 patients resistant to imatinib and in five out of six patients intolerant to imatinib.

Complete haematological responses to bosutinib therapy also occurred across a range of mutations and in patients who had failed to respond to other tyrosine-kinase inhibitors.

Results of a phase I trial of another second-generation tyrosine-kinase inhibitor, 1NNO-406, were also presented at the meeting. These showed that INNO-406 is well tolerated and led to responses in patients in whom treatment with other tyrosine-kinase inhibitors had failed.