Background: Combination of cytotoxic chemotherapy with a tyrosine kinase inhibitor is effective in the treatment of Ph+ ALL. Ponatinib is a more potent BCR-ABL1 inhibitor than imatinib and dasatinib. The combination of chemotherapy with ponatinib might improve response rate and clinical outcome. Methods: In this phase II trial, 52 pts with newly diagnosed Ph+ ALL received 8 cycles (cy) of HCVAD alternating with high-dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cy 1 then continuously for the subsequent 7 cy at the dose of 30 mg then 15 mg once a CMR is achieved. Pts in CMR received maintenance with ponatinib and vincristine and prednisone monthly for 2 years followed by ponatinib. Results: To date 49 pts with untreated Ph+ ALL and 3 previously treated (2 with prior cy of chemotherapy before Ph+/BCR-ABL status was known not in CR, and 1 post HCVAD-dasatinib in CR) have a median follow-up of 31 months (1-50) (table 1). All pts were in CR after cy 1. 42 of the 46 (91%) with Ph+ metaphases achieved a CCyR after 1 cy; 2 had a minor cytogenetic response only and 2 had no cytogenetic analysis at CR, both of them achieved a CCyR after cy 2. To date, 50 (96%) have achieved a MMR, of whom 41 (79%) have achieved a CMR at a median of 10 weeks from initiation of treatment (2 -96). MRD status by flow cytometry is negative in 50 of the 51 (98%) at a median of 3 weeks (2-14). Median time to neutrophil and platelet recovery for cy 1 was 18 and 22 days, and 16 and 22 days for subsequent cy, respectively. 10 underwent allogeneic transplantation after a median of 4 cy (3-19). 2 had grade 5 vascular events (VE) with no underlying risk factors (1, MI; 1, NSTEMI). No further VE were reported with ponatinib dose optimization. The 3-y CR duration and OS rates were 79% and 82%, respectively. Conclusions: The combination of HCVAD with ponatinib is safe and effective in achieving molecular remissions in pts with Ph+ ALL. Clinical trial information: NCT01424982