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).

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.

A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL….Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib...Supplemental Table 3 - Summary of Dasatinib Treatment Responses, Prior Imatinib Response and Bcr/Abl Genotype in Chronic Phase Patients.

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.

Overall, these data indicate that the ENU-based assay faithfully reproduces the spectrum of mutations seen in patients with clinical resistance to imatinib mesylate...Spectrum and frequency of BCR-ABL kinase domain mutations recovered in the presence of imatinib mesylate, nilotinib, and dasatinib...Although both dasatinib and nilotinib are much more potent than imatinib mesylate and have activity against most kinase domain mutants, it is conceivable that their specific modes of binding to Abl may lead to new “vulnerable” sites that could confer drug resistance.

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%).