In a study of 11 patients with advanced-stage chronic myeloid leukemia (or Philadelphia chromosome positive acute lymphoid leukemia) who relapsed during treatment with the kinase inhibitor STI-571 (Gleevec), our group reported BCR-ABL gene amplification and kinase domain mutation as potential mechanisms of resistance (1). Specifically, three patients had gene amplification and six patients had a point mutation resulting in a threonine-to-isoleucine change at amino acid position 315 (T315I) of the ABL kinase domain. Subsequently, Technical Comments were published from two groups (Barthe et al. and Hochhaus et al.) who reported that they were unable to detect the T315I mutation in such patients (2). Both groups did, however, detect kinase domain mutations in a different residue in two patients (E255K and E255V).

As described in abstracts for the 2001 Annual Meeting of the American Society of Hematology, four groups, including Hochhaus and colleagues (3), have now detected patients with the T315I mutation (3, 4). All the groups, including ours, have detected additional kinase domain mutations. The overall contribution of these mutations versus other potential resistance mechanisms remains to be defined.