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.

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.

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.