Abstract Introduction: Ponatinib, a potent third-generation TKI, is an effective treatment for refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Data from single-center studies suggest that ponatinib combined with multi-agent chemotherapy improves long-term outcomes compared to earlier generation TKIs. While hematopoietic stem cell transplantation (HSCT) is often recommended for Ph+ ALL, studies have shown that achieving early minimal residual disease (MRD) negativity with TKI-based chemotherapy may obviate the need for transplantation. However, real-world data on the effectiveness of ponatinib in routine clinical practice in Japan are limited. Methods: We conducted a retrospective analysis using the “Medical Data Vision” Diagnosis Procedure Combination (DPC) database. We identified 439 adult Ph+ ALL patients treated with ponatinib as second- or third-line TKI therapy between November 2016 and September 2023. We collected data on patient demographics, Charlson Comorbidity Index (CCI), prior TKI treatments, and HSCT status. Overall survival (OS) from the initiation of ponatinib was estimated using the Kaplan-Meier method, and prognostic factors were evaluated using a Cox proportional hazards model. Results: A total of 439 patients were analyzed (51.3% male; median age, 64.0 years). The median CCI was 7. Dasatinib was the TKI most frequently used prior to ponatinib (76.3%) during this research period. HSCT was performed in 52 patients (11.8%), with the proportion of transplants decreasing with age (21.6% in ages 18-55 vs. 2.8% in ages ≥65). The 1- and 3-year OS rates for the entire cohort were 77.1% and 63.4%, respectively. Survival was strongly stratified by age, with 3-year OS rates of 80.6% for patients aged 18-55, 58.0% for ages 56-64, and 54.3% for ages ≥65. Higher CCI scores were associated with significantly lower OS (log-rank test: p0.001). Ponatinib administered as a second-line therapy resulted in significantly better OS compared to third-line therapy (log-rank test: p0.001, 3-year OS: 67.3% vs. 48.3%). Cox proportional hazards analysis identified age and the number of prior TKI treatments as independent prognostic factors for OS. The cumulative incidence of arterial occlusive events (AOEs) at 5 years was approximately 40% in patients aged ≥65.Conclusion: This large, real-world database study reveals favorable survival outcomes for Japanese patients with Ph+ALL treated with second- or third-line ponatinib, including elderly patients. The long-term survival in younger patients (18-55 years) appears promising, potentially reaching a plateau without HSCT. However, the cardiovascular risk in the elderly highlights the importance of managing comorbidities and considering antiplatelet therapy. Earlier administration of ponatinib was associated with improved survival, underscoring its importance in the treatment sequence for Ph+ ALL.
Yanai et al. (Mon,) studied this question.