Background: Ponatinib and blinatumomab are both active in Ph+ ALL. A combination of these agents may lead to durable remissions when given in the frontline setting and may eliminate the need for chemotherapy or stem cell transplant (SCT). Methods: In this phase II study, patients (pts) with newly diagnosed Ph+ ALL received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for at least 5 years. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Pts also received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2023, 54 pts were with newly diagnosed Ph+ ALL were treated. Baseline characteristics are shown in the table. Among 35 pts evaluable for hematologic response, 23 (97%) achieved CR/CRi; 1 pt had early death. Among 48 pts evaluable for molecular response, 34 (71%) achieved CMR after 1 cycle, and 43 (90%) achieved CMR at any time. After 2 weeks of therapy, 18/35 tested pts (51%) achieved CMR in the peripheral blood. 34/38 tested pts (89%) achieved MRD negativity by next-generation sequencing at a level of 10^-6. Four of these pts who were MRD-negative by NGS had detectable low-level BCR:ABL1 transcripts by PCR at the same time (ranging from 0.01% to 0.05%). The median follow-up is 16 months (range, 1-55 months). Three patients relapsed after a median of 9 months of remission (range, 8-23 months), 1 in bone marrow with new E225V mutation and 2 extramedullary-only. Three pts have died (1 from intracranial hemorrhage, 1 from post-procedural hemorrhage, and 1 from brain aneurysm). There have been no leukemia-related deaths, the estimated 2-year EFS and OS are both 90%. Only 1 pt underwent SCT in first remission; this pt was transplanted due to persistently low-level BCR:ABL1 positivity. Among the 47 pts in ongoing remission without SCT, the median duration of response is 15 months. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in 2 patients due to possibly related adverse events (CVA and coronary stenosis in 1 pt each). Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab is safe and effective in newly diagnosed Ph+ ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for SCT. Clinical trial information: NCT03263572.