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.