MRD-guided outcome analysis of ponatinib plus hyper-CVAD versus historical imatinib in ph-positive ALL: Impact of early response and dose-adjusted ponatinib

Abstract Background : The treatment strategies and outcomes of Philadelphia chromosome (Ph)-positive ALL have markedly improved with the development of tyrosine kinase inhibitors (TKIs), particularly with the introduction of ponatinib. Hyper-CVAD plus ponatinib frontline therapy was evaluated in a phase 2 clinical trial and proved its efficacy with long-term follow-up. While its frontline efficacy has been established in trials, real-world data comparing ponatinib-based regimens with historical imatinib-based therapy are limited. Moreover, the clinical significance of early measurable residual disease (MRD) response and ponatinib dose adjustment remains unclear. Aims To evaluate MRD-guided treatment outcomes in newly diagnosed Ph-positive ALL treated with ponatinib plus hyper-CVAD versus historical imatinib-based protocols, with a focus on early MRD response and ponatinib dose adjustment. Methods We retrospectively analyzed 193 newly diagnosed Ph-positive ALL treated with imatinib plus hyper-CVAD (n=158, 2018-2022) or ponatinib plus hyper-CVAD (n=35, 2023-2024), followed by allo-HCT if CR was achieved and donor was available. MRD was assessed via RT-qPCR targeting BCR::ABL1after remission induction (TP1, 4–6 weeks), after the first consolidation (TP2, 10–12 weeks), after the second consolidation (TP3, 16–20 weeks, typically pre-HCT), and post-HCT. Ponatinib was reduced from 30 mg to 15mg daily in patients achieving complete molecular response (CMR); others continued 30 mg. Results After excluding early deaths in each group (imatinib 10 [6.3%] and ponatinib 2 [5.7%]), 148 imatinib frontline and 33 ponatinib frontline protocols were evaluated and compared. At TP2, ponatinib achieved higher CMR rates (57.5% vs. 46.6%) and significantly lower poor molecular response (PMR) (6.0% vs. 25.7%, P=0.011). One-year progression-free survival (PFS) was superior with ponatinib (74.2% vs. 39.2%, P<0.001), with a lower cumulative incidence of MRD/hematologic relapse (CIMR: 26.7% vs. 52.0%, P=0.001). The 1-year overall survival (OS) was 93.3% with ponatinib and 82.4% with imatinib (P=0.103). Good MRD responders at TP2 did not show significantly different CIMR between imatinib 400mg and ponatinib 15mg subgroups (36.2% vs.21.8%, P=0.192), but patients with poor MRD response at TP2, continued ponatinib 30 mg significantly reduced CIMR (22.1% vs. 65.8%, P=0.003) compared to imatinib 400mg. In the imatinib and ponatinib subgroups, 126 (85.1%) and 30 (90.9%) underwent allogeneic-HCT in CR (P=0.305). Pre-HCT CMR was higher with ponatinib (76.7% vs. 53.9%, P<0.001), and post-HCT 1-year PFS also favored ponatinib (75.7% vs. 50.7%). Conclusion Ponatinib plus hyper-CVAD showed significantly improved MRD response and superior PFS with low CIMR compared to historical imatinib-based frontline therapy in patients with Ph-positive ALL. After TP2, MRD-guided ponatinib dose adjustment—particularly maintaining 30 mg in poor responders—demonstrated favorable outcomes. These findings support MRD-directed, dose-adapted ponatinib strategies to optimize disease control in high-risk Ph-positive ALL.