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.

CONTRADICTING EVIDENCE: Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. High response rates were observed in patients with the majority of different BCR-ABL mutation types, including highly imatinib-resistant mutations in L248, Y253, E255, F359, and H396, in addition to other common mutations in G250 and M351 (Figure 4).

Mutations were identified in 60 (60%) of these patients (all with imatinib-resistant CML-AP). Despite the presence of imatinib-resistant BCR-ABL mutations and their association with poor prognosis, at 8 months' follow-up, 73% of patients with an imatinib-resistant BCR-ABL mutation had achieved MaHR following treatment with dasatinib.

CONTRADICTING EVIDENCE: Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily. The number of patients with BCR-ABL mutations before study treatment was 88 (56%) of 156, and 29 different mutations were detected. As noted previously,17 patients with a preexisting T315I mutation (n = 9) did not respond to dasatinib therapy (Table 3). Few CCyRs were observed in patients with F317L (0 of four) or E255K (one of eight) mutations.

BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS354825 prolongs survival of mice with BCR-ABL– driven disease and inhibits proliferation of BCR-ABL–positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML....In vitro analysis of cell-growth inhibition of imatinib-resistant Ba/F3 cells expressing the indicated BCR-ABL mutants. Viable cell counts were performed in triplicate after 48 hours of exposure to BMS-354825 and normalized to the dimethyl sulfoxide–treated sample.

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%).

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.