The Pharmaceutical Journal
Vol 276 No 7384 p66
21 January 2006

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Dasatinib effective in treating resistant CML cases

Dasatinib, a novel tyrosine kinase inhibitor, is effective in imatinib-resistant and intolerant patients with chronic myeloid leukaemia (CML), according to data from a phase II trial presented at the 47th annual meeting of the American Society of Hematology, held in Atlanta, Georgia, last month.

Imatinib (Glivec), which inhibits the abnormal BCR-ABL fusion protein, has transformed treatment of CML. However, the development of resistance in some patients has led to the search for second generation inhibitors. Studies have shown that dasatinib exerts activity against 18 of 19 imatinib-resistant BCR-ABL mutants.

Andreas Hochhaus, from the University of Heidelberg, Mannheim, Germany, presented data for 186 patients with chronic phase CML resistant to imatinib. At six months 90 per cent reached a complete haematological response (defined as control of white blood cell counts) and 45 per cent achieved a major cytogenetic response (defined as elimination of cells with the Philadelphia chromosome).

Francois Guilhot, from the University Hospital, Poitiers, France, presented data for 99 patients with accelerated phase chronic CML, resistant to imatinib. Results showed 59 per cent achieved a major haematological response and 31 per cent a major cytogenetic response.

Finally, Moshe Talpaz, from MD Andersen Cancer Centre, Houston, Texas, presented data for 68 patients with chronic CML in blast crisis. He showed 31 per cent reached a major haematological response and 29 per cent achieved a major cytogenetic response.

“Significant improvements of haematologic and cytogenetic responses were seen in pretreated CML patients in all phases of the disease,” said Dr Hochhaus.

Other inhibitors
Data on AMN 107, an oral inhibitor of BCR-ABL and 32 of 33 mutant forms of protein responsible for the development of CML, were also presented at the ASH annual meeting. The investigational compound displayed significant activity in patients with imatinib-resistant CML or Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL).

In a phase I trial involving 119 patients, those with CML and a BCR-ABL mutation achieved a 60 per cent haematological response and a 41 per cent cytogenetic response. Those without the mutation achieved a 72 per cent haematological response and a 59 per cent cytogenetic response. A lower response of 33 per cent was achieved in Ph+ ALL patients with a BCR-ABL mutation.

Meanwhile, researchers have identified a new class of BCR-ABL inhibitors that target tyrosine kinase activity by a distinct mechanism (published online in Nature Chemical Biology on 25 December 2005). Compounds in this class, such as GNF-2, inhibit BCR-ABL kinase activity through an allosteric non-ATP competitive mechanism (unlike dasatinib and AMN 107). They have a high degree of cellular and enzymatic specificity and are active against resistant mutants, making them “interesting candidates as the starting point for new drug development”.