Background: Ponatinib is a potent oral pan–BCR-ABL TKI that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in pts with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in this analysis (data as of 15 Oct 2013). Median follow-up was 33 (0.5–57) mos. NCT00660920. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline BCR-ABL mutations (29% with T315I). 38% (58% chronic phase [CP] CML) of pts remained on study. Adverse events (AEs) and progression were the most common reasons for discontinuation in Ph+ pts (20% and 17%, respectively. The most common treatment-emergent AEs were rash (52%), fatigue (52%), abdominal pain (51%), headache (48%), arthralgia (46%). Treatment-emergent vascular occlusive events were observed in 23% (serious events) and 37% (all events) of pts, including cardiovascular, peripheral vascular, cerebrovascular, and venous thrombotic events [serious (all)] in 15% (23%), 5% (9%), 5% (8%), and 0% (5%). Significant anti-leukemic activity was observed; among CP-CML pts, major cytogenetic response (MCyR), complete cytogenetic response (CCyR), and major molecular response (MMR) rates were 72%, 65%, and 51%, respectively; 75% of pts with MCyR, 69% with CCyR, and 53% with MMR are estimated (Kaplan-Meier [KM]) to maintain response for at least 3 yrs (4 yr KM estimates: 75% MCyR, 53% MMR). Of 28 CP-CML pts with CCyR, 23 remained on study (17 with continuous CCyR); of 22 pts with MMR, 20 remained on study (12 with continuous MMR). Conclusions: Substantial and durable responses were observed with ponatinib in heavily pretreated CP-CML pts. Vascular occlusive events were observed. Risk and benefit considerations should be evaluated when utilizing ponatinib in this pt population. Clinical trial information: NCT00660920.