Beyond imatinib: Real-world mortality patterns across modern second-line TKIs in CML.

e18594 Background: Tyrosine kinase inhibitors (TKIs) have altered management and outcomes of chronic myeloid leukemia (CML). Imatinib has been a common first-line TKI for several decades, but some patients discontinue this agent due to intolerance or poor hematologic or molecular response and are switched to second-line TKIs including nilotinib, bosutinib, dasatinib, or ponatinib depending on side effect profiles and mutational analysis. Randomized trials have established the effectiveness of second-line TKIs, but comparative real-world survival outcomes after imatinib discontinuation are not as established. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, which includes electronic health records from several healthcare organizations. Adult patients (>18 years) with BCR-ABL positive CML who received imatinib and subsequently started on a second-line TKI were identified. The index date was defined as initiation of the second-line agent after imatinib exposure. Patients treated with dasatinib, bosutinib, ponatinib, or asciminib were compared with those receiving nilotinib. Nilotinib was selected as the reference as it had the largest available cohort size. The primary outcome was all-cause mortality. Pairwise comparisons were performed using 1:1 propensity score matching for demographics and major comorbidities. Survival was assessed using Kaplan-Meier analysis with hazard ratios and log-rank testing. Results: After matching, cohort sizes ranged from 320 to 662 patients in each group. Mortality did not significantly differ between dasatinib and nilotinib (15.5% vs 14.8%; HR 1.17) or between bosutinib and nilotinib (21.5% vs 23.6%; HR 1.07). Asciminib cohort was associated with lower mortality (9.2% vs 21.8%), but Kaplan-Meier survival analysis did not reveal a statistically significant difference. In contrast, ponatinib was associated with higher mortality compared with nilotinib (28.8% vs 20.0%; HR 2.00, 95% CI 1.45–2.76; p<0.001). After matching, baseline characteristics were well balanced. Conclusions: In this large real-world cohort of patients with CML who discontinued imatinib, survival outcomes after second-line TKI therapy were similar among dasatinib, bosutinib, and nilotinib, while asciminib illustrated lower mortality. The higher mortality seen with ponatinib could be due to the differences in underlying mutation profiles or this drug's side effects. These findings provide real-world data which supports existing trials and reassures individual selection of second-line TKIs after discontinuing imatinib.