Target Trial Emulation of Second-Generation Versus First-Generation Tyrosine Kinase Inhibitors in Adult Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

PURPOSE Philadelphia chromosome–positive acute lymphoblastic leukemia accounts for approximately 20%-30% of adult acute lymphoblastic leukemia and remains associated with relapse despite imatinib-based therapy. We compared the effectiveness and safety of first-generation versus second-generation tyrosine kinase inhibitors (TKIs) in adults with newly diagnosed disease. METHODS We conducted a retrospective target trial emulation using TriNetX electronic health record data from January 2014 to February 2025. Adults age 18 years or older with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia were eligible. After exclusions, 2,764 patients were clinically eligible; 2,295 met the as-started exposure definition for the primary comparison. Propensity score matching yielded 592 patients per arm comparing imatinib with second-generation TKIs, predominantly dasatinib. RESULTS At a median follow-up of 1,140 days for the second-generation cohort versus 1,129 days for imatinib, second-generation TKIs were associated with improved overall survival (hazard ratio, 0.677 [95% CI, 0.544 to 0.842]; P < .001) and lower 5-year mortality (26.4% v 38.7%; risk ratio, 0.681 [95% CI, 0.576 to 0.806; P < .001). Findings were consistent in on-treatment and US-only analyses. Benefit was significant in patients age 18-34 and 35-64 years and with dasatinib, but not in patients age 65 years or older. Selected neurologic, hematologic, GI, and cardiometabolic toxicities were more frequent with second-generation therapy but did not offset the survival advantage. CONCLUSION Second-generation TKIs, particularly dasatinib, may be considered as frontline therapy for many adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia, particularly those younger than 65 years.