Ponatinib Monotherapy in Adult Patients with Relapsed or Refractory Philadelphia-Positive Acute Lymphoblastic Leukemia: A Real-World Retrospective Analysis Including Measurable Residual Disease Relapse

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Introduction: The treatment of relapsed or refractory (R/R) Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) remains challenging after failure to several tyrosine kinase inhibitors. This study evaluated the clinical outcomes of ponatinib in a real-world cohort with R/R Ph-positive ALL, including those treated at the stage of measurable residual disease (MRD) relapse. Methods: We retrospectively analyzed 79 adults with R/R Ph-positive ALL treated with ponatinib monotherapy. At the start of treatment, 55 patients (69.6%) were in hematologic relapse, while 24 (30.4%) were in MRD relapse. We evaluated complete remission (CR) rate, MRD response, survival outcomes, and predictors of response and survival according to various clinical and genetic parameters. Results: CR was achieved in 48 (60.7%) patients, and 22 of 46 with MRD data (47.8%) achieved complete molecular response. Ponatinib initiation at MRD relapse was associated with higher odds of better molecular response. In multivariate analysis, age under 60 and MRD response better than major molecular response were linked to improved overall survival (OS). However, 2-year OS remained poor at 29.5% (95% CI: 18.9–40.9%). Allo-HCT was performed in 38 patients (48.1%), with a 2-year post-transplant OS of 29.1% (95% CI: 12.9–47.6%). Prior allo-HCT was associated with inferior OS and disease-free survival. Conclusion: Ponatinib achieved an acceptable CR rate and MRD response in R/R Ph-positive ALL, but long-term survival remained poor despite allo-HCT. These results support earlier use of ponatinib in the salvage setting and highlight the need for combination strategies to overcome the limited durability of monotherapy in patients with R/R Ph-positive ALL.