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...Nilotinib…T315I, Y253H, E255K/V, or F359V/C/I or G250E

The most common mutations associated with progression were the E255K/V, F359C/V, Y253H, and T315I mutations.

...A total of 51 ABL mutations were observed in 37 of 91 patients who had a baseline assessment for mutational status. Nilotinib was active in patients with and in those without mutations...Two patients with a T315I mutation (one with chronic-phase CML and one with blastic-phase CML) had no response to nilotinib.

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%).

...which shows a model of AMN107 in complex with Abl kinase mutant M351T, and shows that the sensitivity of Bcr-Abl mutants to AMN107 segregates into four categories: high (IC50 ≤ 70 nmol/L: M244V, G250E, Q252H, F3llL, F317L, M351T, V379I, L387M, H396P, H396R), medium (IC50 ≤ 200 nmol/L: Y253F, E255K, F359V), low (IC50 ≤ 450 nmol/L: Y253H, E255V), and insensitive (IC50 > 2 μmol/L: T315I)....As expected, T315I was completely insensitive to AMN107 treatment (IC50 > 5,000 nmol/L)...