Is AMN-107 a step forward from imatinib in the treatment of chronic myeloid leukaemia?

The Philadelphia (Ph) chromosome was the first consistent chromosome abnormality identified in cancer. It is found in 90% of patients with chronic myeloid leukaemia (CML) and in a subset of patients with acute lymphoblastic leukaemia. The effectiveness of the Bcr-Abl kinase inhibitor imatinib in these conditions reduces with advancing disease and/or the development of resistance to imatinib. AMN-107 inhibited the proliferation of haematopoietic cells expressing the mutants in Ph+ CML and acute lymphoblastic leukaemia with concentrations causing 50% inhibition of approximately 12 nM, making it more potent than imatinib. AMN-107 was also effective against several imatinib-resistant Bcr-Abl mutants, but not T3151. In mice transduced with Bcr-Abl, AMN-107 reduced mortality and tumour burden. In mice transduced with the E255V imatinib-resistant mutant of Bcr-Abl, AMN-107 delayed the onset of leukaemia. As AMN-107 is more potent and more selective for Bcr-Abl than imatinib, it may represent a step forward in the treatment of CML, but further animal (and then clinical) studies are needed to test this.