Outcomes with ponatinib in patients with relapsed/refractory Philadelphia-chromosome positive acute lymphoblastic leukemia: A systematic review and meta-analysis

Abstract Introduction: Outcomes in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) have improved significantly with the introduction of tyrosine kinase inhibitors (TKIs); however, relapse remains common, and resistance to first- and second-generation TKIs poses a major therapeutic challenge. Ponatinib, a third-generation TKI, has emerged as a viable option for patients with relapsed or refractory (R/R) Ph+ ALL. This systematic review and meta-analysis aimed to evaluate its clinical outcomes and safety profile in this setting. Methods: A systematic search was conducted in PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov (from inception to May 2025) following PRISMA guidelines. Search terms included “Philadelphia-chromosome-positive acute lymphoblastic leukemia,” “relapsed/refractory,” and “Ponatinib.” After screening 529 references, five studies met the inclusion criteria: original research evaluating Ponatinib monotherapy in R/R Ph+ ALL with reported outcomes. Meta-analyses were conducted using a random-effects model for outcomes reported in two or more studies. Pooled prevalence estimates were reported with 95% confidence intervals (CIs), and heterogeneity was assessed using the I² statistic. Results: Five studies with a total of 469 participants were included: two retrospective, one prospective, one observational, and one post-marketing surveillance study. The median patient age was 56 years (range: 18–91), and 58% (n = 252) were male. Most had prior exposure to TKIs (96.5%, n = 443), and 28% (15/53) had undergone prior allogeneic hematopoietic stem cell transplantation (allo-HCT). The pooled complete remission (CR) rate was 86% (95% CI: 66–99%, I² = 29.5%), and the 1-year overall survival (OS) rate was 69% (95% CI: 64–73%, I² = 0.0%). Median overall survival ranged from 1.7 to 58.7 months across studies, and one study reported a 3-year progression-free survival rate of 48.9. The pooled rate for patients who underwent allo-HCT after Ponatinib was 27% (95% CI: 17–41%, I² = 0.0%). The pooled rate for non-responders to Ponatinib was 15% (95% CI: 2–34%, I² = 0.0%). The pooled adverse event (AE) rate was 53% (95% CI: 40–65%, I² = 47.9%). Commonly reported adverse events included thrombocytopenia (67%), neutropenia (44%), cytokine release syndrome (CRS) (11.5%), and immune effector cell-associated neurotoxicity syndrome (ICANS) (23%). Conclusion: Ponatinib appears to be an effective treatment option in relapsed/refractory Ph+ ALL, demonstrating favorable remission and 1-year survival outcomes with manageable toxicity. Further prospective trials with larger sample sizes and longer follow-up are needed to establish its optimal use and long-term efficacy.