Treatment recommendations based on BCR-ABL1 mutation profile...The table below lists the BCR-ABL1 mutations that should not be treated with bosutinib, dasatinib or nilotinib in the second-line setting…Dasatinib…T315I/A, F317L/V/I/C, or V299L

In particular, V299L, T315A and F317L/V/I/C are resistant to dasatinib. Y253H, E255K/V and F359V/C/I are resistant to nilotinib, and V299L to bosutinib.

In our study, we investigated the activity of bosutinib, dasatinib, imatinib, and nilotinib against a panel of 18 mutated forms of BCR/ABL associated with imatinib resistance in CML and Ph+ acute lymphoblastic leukemia patients. The results are listed in Figure 1 (Table 1 lists all the actual values for the relative concentration that inhibits 50%).

To validate that the mutants recovered played a causal role in BMS-354825 resistance, we generated individual BCR-ABL retroviral constructs containing the point mutation of interest, introduced these into Ba/F3 cells, and measured the IC50 for growth in BMS-354825...Of note, these three mutants were the most frequently recovered in our screen. L248R, E255K, F317L, and the previously uncharacterized mutant V299L show modest changes in IC50, increasing ≈10- to 15-fold from WT BCR-ABL….IC50 for growth of Ba/F3 stable lines grown in the presence of BMS-354825 and imatinib.

At 5 nM dasatinib mutations of L248, Q252, E255, V299, T315, and F317 were recovered (Table 1)…Spectrum and frequency of BCR-ABL kinase domain mutations recovered in the presence of imatinib mesylate, nilotinib, and dasatinib.