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Abstract Background: Patients with chronic phase chronic myeloid leukemia (CP-CML) who have failed treatment with two prior tyrosine kinase inhibitors (TKIs) face limited treatment options. This challenge is particularly pronounced in patients harboring the T315I mutation, a known driver of resistance to second-generation (2G) TKIs. Ponatinib, a third-generation TKI, is approved for adult patients with CP-CML who are resistant or intolerant to at least two prior TKIs or have T315I-positive disease. This study presents a model-based evaluation of the long-term clinical outcomes of ponatinib versus 2G TKIs in this setting. Objectives: To estimate and compare ponatinib versus 2G TKIs (bosutinib, dasatinib, nilotinib) in adult patients with CP-CML who have received two prior TKIs, focusing on long-term clinical and economic outcomes: survival (life years), quality-adjusted survival (QALYs), and healthcare resource utilization (outpatient, inpatient and emergency department visits). Methods: A decision-analytic model was developed using a hybrid structure: a decision tree to stratify patients by T315I mutation status, followed by partitioned survival models (PSMs) to estimate long-term outcomes. The PSMs included three health states: progression-free (PF), progressed disease (PD), and death. The PF state was further divided into two sub-states based on complete cytogenetic response (CCyR) status. In the absence of randomized clinical trials directly comparing ponatinib with 2G TKIs, the model utilized data from a retrospective analysis of CP-CML patients without the T315 I mutation treated at the MD Anderson Cancer Center, as well as subsets of patients from the PACE and OPTIC trials. Kaplan-Meier curves for progression-free and overall survival were extrapolated to predict lifetime outcomes. For the T315I-positive population, the survival curves were adjusted using hazard ratios derived from the PACE study data and published literature. Treatment response was incorporated to reflect differences in quality of life and healthcare resource within the PF state. Resource use inputs were based on a US – specific retrospective cohort study using IBM® MarketScan® Commercial Claims and Medicare Supplement Databases. Health related quality of life inputs utilities were sourced from published literature. The model adopted a lifetime horizon with 3-month cycles and applied a 3% annual discount rate. Parameter uncertainty was addressed through probabilistic sensitivity analysis, with outcomes reported as the mean values derived from 1,000 simulations. Results: Model projections over a lifetime horizon indicate that ponatinib improves clinical outcomes compared to 2G TKIs. In the non-T315I population, median progression-free survival (PFS) was 195 months (95% CI, 192-199) with ponatinib versus 56 months (95% CI, 54-58) with 2G TKIs. Among patients with the T315I mutation, ponatinib achieved a median PFS of 148 months (95% CI, 144-151), compared to 13 months (95% CI, 12-14) with 2G TKIs. The model demonstrated that ponatinib yielded an incremental gain of 4.6 life years (95% CI, 4.5-4.8) and 3.9 QALYs (95% CI, 3.8-4.1). Additionally, within the first five years of treatment, ponatinib reduced healthcare resource use by preventing 1.6 outpatient visits (95% CI, 1.4-1.9) and 2.9 inpatient days (95% CI, 2.8-3.0) per patient. Conclusions:This model-based analysis suggests that ponatinib offers substantial clinical benefits over 2G TKIs in the third-line treatment of CP-CML, particularly for patients with the T315I mutation. These findings support the clinical value of ponatinib as a preferred treatment option in this setting, with the potential to improve survival outcomes and reduce burden to the healthcare system.