Front‑line ponatinib vs imatinib in newly diagnosed Philadelphia‑positive ALL: Systematic review and meta‑analysis of survival and deep molecular response

Abstract Front-Line Ponatinib Versus Imatinib in Newly Diagnosed Philadelphia-Positive ALL: A Systematic Review and Meta-Analysis Background: Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) carries a historically poor prognosis, with five-year overall survival (OS)—the time from initiation of therapy to death from any cause—remaining below 40 % when first-line treatment relies on imatinib. Deeper molecular remissions, measured as complete molecular response (CMR; BCR::ABL1 transcript ≤ 0.01 %), correlate strongly with long-term survival. Ponatinib, a third-generation BCR::ABL1 inhibitor active even against the T315I mutation, may achieve higher CMR rates and translate into superior OS if used up-front, but direct comparisons to imatinib have been limited. Methods: We searched MEDLINE, Embase, CENTRAL, conference proceedings, and trial registries through July 2025 using PRISMA guidelines for studies of first-line ponatinib versus imatinib in untreated adult Ph + ALL reporting hazard ratios (HRs) for OS or odds ratios (ORs) for CMR. After screening 639 records (516 post-deduplication) and 24 full texts, four reports met inclusion: the PHALLCON phase 3 RCT (154 ponatinib vs 78 imatinib), a matching-adjusted indirect comparison (MAIC; three contrasts; effective n ≈ 305), a PRO substudy (125 vs 62), and one protocol. Two reviewers extracted data, assessed bias (RoB 2 for RCTs; ROBINS-I for nonrandomized), and pooled log-HRs and log-ORs using inverse-variance random-effects models (DerSimonian–Laird), with fixed-effect sensitivity. Heterogeneity was quantified by I²; certainty by GRADE. Results: A total of 316 patients contributed OS data from PHALLCON and the MAIC. The pooled random-effects HR for OS was 0.52 (95 % CI 0.24–1.11; I² = 56 %), indicating a 48 % relative reduction in the risk of death with ponatinib versus imatinib, although the confidence interval crossed unity; the corresponding fixed-effect HR was 0.53 (0.32–0.87). Within PHALLCON alone, the HR was 0.76 (0.38–1.52). For CMR, 505 patients across four contrasts (PHALLCON and three MAIC pairs) were evaluable. PHALLCON reported CMR rates of 34 % (53/154) with ponatinib versus 17 % (13/78) with imatinib by the end of cycle 3. The pooled random-effects OR for achieving CMR was 5.14 (2.57–10.29; I² = 40 %), with a fixed-effect OR of 4.46 (2.76–7.19), indicating more than a fivefold higher likelihood of deep molecular remission. In PHALLCON, arterial-occlusive events occurred in 5.2 % versus 3.8 % of patients (risk difference +1.4 percentage points), grade ≥ 3 alanine aminotransferase elevations in 9.1 % versus 3.8 % (+5.3 pp), and any grade ≥ 3 adverse event in 74 % versus 60 %. In the PRO substudy, patients receiving ponatinib experienced clinically meaningful improvements in quality of life, with least-squares mean increases in the FACT-Leu Total Outcome Index of +6.21 points (1.67–10.75) at induction and +7.25 points (1.98–12.52) at consolidation, exceeding the established 4-point minimal important difference. GRADE assessment rated the certainty of CMR evidence as moderate (downgraded for indirectness; upgraded for large magnitude of effect) and OS evidence as low (downgraded for risk of bias in the MAIC and imprecision of the pooled estimate). Conclusions: This meta-analysis demonstrates that up-front ponatinib substantially increases the likelihood of achieving deep molecular remission and trends toward reducing mortality compared with imatinib in adults with newly diagnosed Ph + ALL. While the survival benefit remains statistically imprecise pending ongoing randomized trials, the magnitude of the CMR advantage and clinically meaningful quality-of-life improvements support considering ponatinib as the preferred first-line TKI in patients with acceptable vascular risk profiles. Further prospective data are required to confirm long-term survival gains and fully characterize the safety profile.