Background: Ponatinib is an oral multiple tyrosine kinase inhibitor and potent pan-BCR-ABL inhibitor. Preliminary phase 1 results suggest substantial activity in BCR-ABL+ patients (pts). In preclinical models, ponatinib also inhibits the FLT3/ITD mutant prevalent in AML with potency similar to that of BCR-ABL (IC50 2 nM). A cohort of pts with AML was enrolled in a phase 1 trial of ponatinib to assess safety and preliminary efficacy in this population. Methods: Pts (≥18 years) with relapsed or refractory AML were enrolled after the recommended phase 2 dose of ponatinib was established in pts with chronic myeloid leukemia (CML). Pts received 45 mg ponatinib orally once daily: trough plasma concentrations are known to exceed the target for inhibition of FLT3/ITD activity (IC50) in cells at this dose. FLT3/ITD mutation status was determined at a central laboratory. Results: Of 81 total pts in this study, 12 were included in the AML cohort. The median age of AML pts was 49 (range 30-72) years. At the time of analysis (Dec 15, 2010), 4 (33%) AML pts remained on study (range 77-143 days) and 8 (67%) discontinued (range 10-97 days) (no discontinuations were treatment related). Seven AML pts had documented FLT3/ITD at baseline, 2 did not carry FLT3 alterations, and 3 pts had inadequate samples for testing; however, these 3 pts had a positive FLT3 status reported by investigative sites. Overall, 7 pts with the FLT3/ITD mutation were FLT3 inhibitor naïve. All pts had treatment emergent AEs consistent with those expected in refractory AML. Three pts had treatment related grade 2 pancreatitis: 1 pt subsequently discontinued due to investigator decision; 2 had the event resolve and continued therapy at a reduced dose. The overall response rate in the AML cohort was 25% (3/12): 2 pts (29%) had CRi and 1 (14%) had PR. All responses observed were in the subset of pts with the FLT3/ITD mutation who were naïve to FLT3 inhibitors: 3/7 (43%). Conclusions: Ponatinib was well‑tolerated in this small group of AML patients; the safety profile was similar to that observed in CML. Evidence of activity in pts with the FLT3/ITD mutation was observed, with a response rate of 43% (3/7) in FLT3 inhibitor naïve pts.