Background: The approved tyrosine kinase inhibitor (TKI)ponatinib is potently active against native and resistant BCR-ABL, including T315I. Methods: The pivotal PACE trial (NCT01207440) evaluated ponatinib (starting dose 45 mg/d) in pts with chronic myeloid leukemia (CML) or Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) refractory to dasatinib or nilotinib, or with T315I. Dose reductions were recommended in Oct ‘13 due to observed arterial occlusive events (AOEs). Efficacy and safety at 4 yrs, as well as by yr for chronic phase (CP) CML pts, are reported (data as of 3 Aug ’15). Exposure-adjusted incidence rates of new AOEs are reported as the no. of events/100 pt-yrs. Results: Of 449 pts, 59% received ≥ 3 prior TKIs. At analysis, 30% of pts (median follow-up 37.3, range 0.1–58.5 mo) and 41% (110/270) of CP-CML pts (48.2, 0.1–58.5 mo) remained on study. Responses continued to deepen over time (Table) despite dose reductions. Estimated 4-yr rates for PFS, OS, and maintenance of MCyR and MMR were 56%, 77%, 82% and 61%, respectively. For advanced phase pts, the estimated 4-yr OS was 51%; median OS for blast phase/Ph+ALL pts: 6.9 mo (95% CI, 5.0-9.2). Common (in ≥ 30% of pts) TEAEs were thrombocytopenia 44%, abdominal pain 43%, rash 42%, constipation 37%, headache 37%, dry skin 36%, fatigue and hypertension 30%. AOE rate/serious AOE rate was 23%/19%, including cardio- 13%/9%, cerebro- 9%/7%, and peripheral-vascular 9%/7%. Of pts with AOEs (n = 104), 38% remained on study. Exposure-adjusted incidence rates of new AOEs fell after the first 2 yrs: 15.5 yr 1, 15.7 yr 2, 10.4 yr 3, and 9.6 yr 4. Nearly 2-yrs after recommended dose reductions, 87% (114/131) and 74% (70/95) of CP-CML pts were estimated to maintain MCyR and MMR, respectively, and 8% (6/75) of all dose-reduced pts without a prior AOE on trial had an AOE. Conclusions: After 4 yrs,heavilypretreated pts continue to show deep and lasting responses on ponatinib, and ~2 yrs post recommended dose reductions, maintenance of response is high, and the incidence of newly occurring AOEs has decreased. Clinical trial information: NCT01207440