Background: The combination of chemotherapy plus a TKI is highly effective in Ph+ ALL. In this phase II study, we evaluated the safety and efficacy of HCVAD in combination with the third-generation pan-BCR-ABL inhibitor, ponatinib. Methods: Patients (pts) with newly diagnosed Ph+ ALL received 8 cycles of HCVAD alternating with high dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1. Initially ponatinib 45 mg daily was given indefinitely beginning at cycle 2. Due to concern for vascular events, a protocol amendment was made in which, beginning in cycle 2, pts in CR received 30mg daily and pts in CMR received 15mg daily. Rituximab and IT chemotherapy were given with the first 4 courses. After 8 cycles of HCVAD, pts in CR received maintenance with ponatinib, vincristine and prednisone for 2 years followed by indefinite ponatinib. Results: 64 pts have been treated, 10 of whom had received prior treatment with another regimen (8 in CR, 2 not in CR). Median age was 48 years (range, 21-80) and median follow-up was 33 months (range, 2-62). Median cycles received was 6 (range, 2-8). 63 pts (98%) achieved CR after 1 cycle; 1 pt achieved CRp. CCyR was achieved in 98%, MMR in 97% and CMR in 77%. Median time to CMR was 10 weeks (range, 2-96). Median times to platelet and ANC recovery in cycle 1 were 22 and 18 days, respectively, and for subsequent cycles were 22 and 16 days, respectively. Grade ≥3 pancreatitis was observed in 12 pts (19%), thrombotic events in 4 (6%) and MI in 3 (5%). 8 pts have died, with 2 deaths attributed to ponatinib (both from MI). No grade ≥3 vascular events occurred after the protocol amendment. 38 pts continue to receive treatment (7 in consolidation, 14 in maintenance and 17 post-maintenance). 10 pts (16%) underwent allogeneic SCT in CR1. 7 pts have relapsed, 3 of whom were still receiving ponatinib. The 3-year continued remission and OS rates were 79% and 76%, respectively. In a landmark analysis at 4 months, CR duration and OS did not differ significantly in pts with or without allogeneic SCT. Conclusions: HCVAD plus ponatinib is highly effective in pts with newly diagnosed Ph+ ALL, resulting in high rates of CMR and promising long-term survival. Clinical trial information: NCT01424982