Target trial emulation of second-generation versus first-generation TKIs in adult patients with Philadelphia chromosome-positive ALL

Philadelphia chromosome-postive acute lymphoblastic leukemia (Ph+ ALL) remains associated with relapse despite imatinib-based therapy. A retrospective target trial emulation using TinNetX electronic health record data from January 2014 to February 2025 compared effectiveness and safety of first-generation versus second-generation TKIs in adults with newly diagnosed Ph+ALL. The analysis included 2295 patients. Propensity score matching yielded 592 patients per arm comparing imatinib with second-generation TKIs, predominantly dasatinib. At a median follow-up of 1140 days for the second-generation cohort and 1129 days for for imatinib, the second-generation TKIs were associated with improved overall survival (HR 0.677; p<0.001) and lower 5-year mortality (26.4% versus 38.7%; RR 0.681; p<0.001). Benefit was significant in patients aged 18-34 and 35-64 yeaars with dasatinib, but not in patients aged 65 years or older. Selected neurologic, hematologic, GI, and cardiomeatabolic toxicities were more frequent was second-generation therapy but did not offset the survival advantage. The authors conclude that second-generation TKIs, particularly dasatinib, may be considered as frontline therapy for many adults with newly diagnosed Ph+ALL, particularly those younger than 65 years.