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Background: Hyper-CVAD is an established regimen for adult ALL that was developed at the MD Anderson Cancer Center (MDACC). However, results can vary across different institutions given the heterogeneity of patient populations and institutional practices. Moreover, while a MDACC study demonstrated that the combination of ponatinib plus hyper-CVAD produced remarkable activity in untreated Ph+ ALL, it remains to be externally validated. We sought to validate those findings in previously untreated adult patients with Ph+ ALL., Methods: This was a retrospective study analyzing the outcomes of previously untreated adult ALL patients treated with hyper-CVAD, with a focus on Ph+ ALL patients treated with ponatinib plus hyper-CVAD., Results: 82 patients were included. The median age was 51 years. The median follow-up was 2.62 years. The 5-year overall survival (OS) and event-free survival (EFS) were 39.5 % and 28.2 %, respectively. For Ph+ ALL patients (n = 13) receiving ponatinib plus hyper-CVAD, 3-year OS and EFS were both 92.3 %. Univariate analysis showed a high WBC and poor-risk cytogenetics to be associated with inferior outcomes, while CD20 + predicted favorable outcomes in B-ALL patients. On multivariate analysis, CD20 + retained significance for Philadelphia-negative (Ph-) ALL. For Ph+ ALL, ponatinib was associated with better OS and EFS on univariate and multivariate analysis., Conclusion: Our data supports the use of ponatinib plus hyper-CVAD as a standard of care regimen for Ph+ ALL. Our outcomes for Ph-ALL and T-cell ALL (T-ALL) show that advances are still needed in the frontline setting, and clinical trial enrollment is recommended., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)