Bcr-Abl mutations in imatinib-resistant CML and Ph+ALL patients (pts) enrolled in a phase I study of AMN107

Abstract

6527 Background: AMN107 is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: The spectrum of mutations in Bcr-Abl was evaluated by direct sequencing of the kinase domain and surrounding regions on samples from pts with imatinib-resistant Ph+ CML or ALL in a phase I study of AMN107 (total daily dose range 50 to 1200 mg administered qd or bid). The template was created by semi-nested PCR using primers in the BCR and ABL regions of the gene. Mutations were correlated with clinical response. Results: Among 119 pts, 86 had both pre and post tx analyses: 39 (45%) had mutations at baseline, of whom 27 (69%) responded. 47 (55%) had no mutation at baseline, of whom 34 (72%) responded. The most common baseline mutations were G250E, E255K/V, E355G, F317L, H396R and M351T. New mutations were found during median follow-up of 112 (6 - 350) days in 37 pts (26 without baseline mutations). New mutations most commonly included F349V, E255K/V, E355G, G250E, M244V and T315I. Of the 37 pts, 30 had evaluations after mutations emerged, and 15 continued to respond for median of 160 (41–351) days. Fourteen mutations not previously reported occurred, 6 at codons with known imatinib resistance mutations resulting in novel amino acid substitutions. Novel mutations in multiple pts and/or multiple timepoints included E344G, F311I, E453K, E459Q and L248L. The T315I mutation was present at baseline in 1 pt who failed to respond and emerged in 4 pts, of whom follow-up was available for 3. Two continued to respond ≥ 80 days after developing the mutation and one progressed when the mutation emerged. Conclusions: AMN107 has clinical activity in pts with Ph+CML/ALL with nonmutated and mutated Bcr-Abl. At AMN107 doses used in this phase I study, new mutations often emerged, but were not a reliable predictor of clinical relapse. [Table: see text]