Second generation TK-Inhibitors
Several phase II trials of Dasatinib and Nilotinib involving patients with CML in various phases have since been published. Remarkably, the rate of hematologic response to Dasatinib and Nilotinib is greater than 90% for chronic-phase patients with imatinib failure. In more advanced phases of the disease 20-40% of patients are refractory to Dasatinib and 30-60% to Nilotinib. Overall, no correlation was observed between the presence of a KD mutation and response in either study, with the exception of T315I invariably predicting primary resistance. Notably, patients carrying native Bcr-Abl and patients with a Dasatinib-sensitive mutation had comparable response rates, whereas patients with mutations that confer intermediate sensitivity to dasatinib in vitro exhibited lower rates of major cytogenetic response (MCR). While preliminary, this analysis strongly suggests that levels of response to Dasatinib will depend on the type of Bcr-Abl KD mutation. With respect to Nilotinib, a similar analysis could not be done since the mutational status of individual patients was not reported. Preliminary data from phase II studies demonstrated that cytogenetic responses to Nilotinib were more frequent in patients harboring KD mutations with low IC50, while several patients with relatively resistant mutations progressed. Thus, the greater the in vitro sensitivity the better clinical responses may be observed. In summary, it appears that the novel TK-inhibitors targeting Abl further enrich the therapeutical armentarium for patients with insufficient clinical response or intolerance to Imatinib.