Abstract

Mutations in the catalytic domain of ABL kinase (AKD) are a major mechanism of resistance to imatinib. Over 70 mutations in more than 50 amino acid residues have been reported to date. The ‘gatekeeper’ mutation, T315I, which causes complete resistance to all three FDA-approved tyrosine kinase inhibitors (TKIs), was reported to be not uncommon among a heterogeneous set of patients who had failed first-line imatinib therapy. In addition, the F317L, V299L, and T315A mutations were reported to convey a high degree of resistance to dasatinib, and higher frequency mutations within the P-loop (Y253H/F, E255V/K) and F359 mutations were associated with a high degree of resistance to nilotinib. We studied the prevalence of AKD mutations in the START-C phase II trial of dasatinib in patients who have failed imatinib (resistance or intolerance). Baseline mutation data were available for 95 of 99 patients with imatinib intolerance, and 274 of 288 patients with imatinib resistance. Of these patients, 13 (14%) with imatinib intolerance and 136 (50%) with imatinib resistance had AKD mutations. Of the 149 patients with mutations, only 3 (2%) had the T315I mutation. A total of 57 (38%) subjects had mutations in the P-loop (between 248–256): 13 patients with Y253H/F (9%), and 6 patients with E255V/K (4%). Four subjects (3%) had the F317L mutation, and 8 (5%) had F359 mutations. No subjects with V299L or T315A mutations were detected at baseline. The rates of complete cytogenetic response (CCyR) were 52% in patients with any mutation, 69% in patients with Y253H/F, 40% among those with E255V/K, 0% for T315I mutations, 0% for F317L mutations, and 50% for F359 mutations. Patients without mutations achieved a 55% rate of CCyR. These results confirm that select P-loop and F359 mutations are sensitive to dasatinib, while F317L and T315I mutations are resistant to dasatinib treatment. However, the overall incidence of these dasatinib-resistant mutants is low. In contrast, nilotinibresistant mutations in the P-loop (Y253H/F, E255V/K) or at F359 are more common, representing 15% and 5% of all patients with mutations, respectively. Therefore, the likelihood of harboring a nilotinib-resistant mutation at the time of imatinib resistance appears higher than the likelihood of harboring a dasatinib-resistant mutation, and suggests mutation testing may become instrumental for choosing between the various second-line TKI inhibitors to optimize outcomes.

Disclosures: Deininger:Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding; Novartis: Consultancy. Mauro:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Matloub:Bristol-Myers Squibb: Employment, Equity Ownership; GlaxoSmithKline: Equity Ownership. Sinha:Bristol-Myers Squibb: Employment, Equity Ownership. Ploughman:Bristol-Myers Squibb: Employment. Liu:Bristol-Myers Squibb: Employment, Equity Ownership. Radich:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

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