Point mutations in the kinase domain (KD) of the Bcr-Abl gene are generally regarded as the most frequent mechanism of resistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) in patients (pts) with chronic myeloid leukemia (CML). Nearly all studies, however, have focused mainly on pts with advanced disease, where resistance is most often observed. Nowadays, the great majority of pts on IM are early chronic phase (ECP) pts receiving IM as front-line treatment. If, on one hand, the IRIS study demonstrated that response rates are high and relapse is infrequent in ECP, on the other hand we still know very little on the contribution of KD mutations to resistance in this subset of pts. Between January 2005 and July 2007 we analyzed for the presence of Abl KD mutations one hundred and two ECP pts on IM who were referred to our laboratory because their response was defined either as ‘failure’ (n=70 pts) or as ‘suboptimal’ (n=32 pts) according to recently published recommendations (Baccarani et al, Blood 2006). Twenty mutations were detected in 17/70 (24%) pts who failed IM. In particular, mutations were observed in 1/2 pts who showed no hematologic response (HR) at 3 months, 1/10 (10%) pts who showed less than partial cytogenetic response (PCgR) at 12 months, 4/25 (16%) pts who showed less than complete cytogenetic response (CCgR) at 18 months, 6/23 (26%) pts who lost CCgR, 5/10 (50%) pts who lost HR. Mutations were M244V (n=2), G250E (n=1), Y253H (n=4), E255K (n=1), T277A (n=1), E279K (n=1), F311I (n=1), T315I (n=1), M351T (n=3), E355D (n=1), F359V (n=1), H396R (n=3). In 7 pts who progressed to accelerated or blastic phase shortly after, four had mutations: Y253H (n=2 pts), E255K (n=1 pt) and T315I (n=1 pt). Four mutations were detected in 4/32 (13%) pts who had a suboptimal response to IM. In particular, a mutation was observed in 1/11 (9%) pts who showed less than PCgR at 6 months and in 3/21 (14%) pts who showed less than CCgR at 12 months. Mutations were E255K, F317L, M351T, F359V. In both groups no correlation was observed between likelihood of mutation selection and Sokal risk score. We conclude that in ECP pts who receive IM as front-line treatment Abl KD mutations are not the major mechanism of drug-resistance, probably because mutations tend to accumulate during the natural course of the disease as a result of a progressively increasing genetic instability and are therefore a feature of CML clinical deterioration rather than a phenomenon observed only against a background of IM exposure. Our data highlight the need to find out which is the actual predominant mechanism(s) of resistance acting in the setting of ECP - which now gathers the overwhelming majority of CML pts on IM therapy - as a mandatory step towards the development of effective second-line treatment strategies.
Disclosure: No relevant conflicts of interest to declare.
Supported by European LeukemiaNet, AIL, AIRC.