Background: PON is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the resistant T315I mutant. The efficacy and safety of PON (45 mg QD) were evaluated in the phase 2 PACE trial. Methods: 449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation were enrolled. Data are as of 3 Sept 2013; median follow-up 24 (0.1-35) mo. NCT01207440. Results: Pts were heavily pretreated: 58% received ≥3 TKIs. 42% remained on study (55% CP-CML). The most common reasons for discontinuation: PD (21%) and AEs (14%, most common was thrombocytopenia, 4%). Table shows response rates at any time. In CP-CML, 89% pts maintained MCyR for at least 2 yr; progression-free survival (PFS) and overall survival (OS) at 2 yr were 67% and 86%. For AP-CML, BP-CML, and Ph+ ALL, OS at 2 yr was 72%, 18%, and 21%, respectively. Most common treatment-emergent AEs (≥30%) were thrombocytopenia (43%), rash (40%), abdominal pain (40%), headache (36%), constipation (36%), dry skin (36%). Pancreatitis and pneumonia were the most common serious AEs (SAEs; both 6%). Vascular occlusive AEs [SAEs] were reported as follows: overall 20% [14%], including cardiovascular 9% [6%], cerebrovascular 6% [4%], peripheral vascular 6% [4%] (collectively arterial thrombotic events, ATEs), venous thromboembolic 5% [3%]. Higher dose intensity, older age, and CV risk factors were associated with a higher likelihood of an ATE; pts with and without CV risk factors experienced these events. OS at 2 years was not reduced in pts with an ATE (73%) vs those without (69%); MCyR in CP-CML pts with vs without ATE was 70% vs 51%. Conclusions: PON has substantial clinical activity in heavily pretreated pts with Ph+ leukemias. PON is an important treatment option for pts in whom the need and benefit outweigh the risk. Clinical trial information: NCT01207440.