Pulmonary Arterial Hypertension Risk With BCR-ABL Tyrosine Kinase Inhibitors: Refining Risk With Nationwide Data

Tyrosine Kinase Inhibitors (TKIs) targeting BCR-ABL are the mainstay of chronic myeloid leukemia (CML) therapy and have ushered in an era of near-normal life expectancy for patients who respond to treatment. 1 Resistance and intolerance to the first TKI, Imatinib, prompted development of second-generation (Dasatinib, Nilotinib, and Bosutinib), thirdgeneration (Ponatinib), and mechanistically distinct first-in-class ABL myristoyl-pocket binding inhibitors (Asciminib).Shortly after the introduction of Dasatinib, case reports linked exposure to pulmonary arterial hypertension (PAH), and subsequent case series and pharmacoepidemiologic surveillance studies have confirmed its recognition as a PAHcausing medication. [2][3]3][4] Reports have also implicated Bosutinib, Nilotinib, and Ponatinib, though evidence to date has been limited to individual cases.In this issue of Circulation, Jambon-Barbara et al leverage nationwide observational data and a target trial emulation approach to evaluate the association between second, third, and next-generation TKI exposure and PAH. 5 This study provides the most robust evidence to date and generates population-level estimates of both relative and absolute PAH risk.These data have important implications for deciphering PAH risk and monitoring and treatment strategies in patients for whom these medications are indicated.The strengths of the study include the use of a large nation-wide dataset with excellent information capture and robust statistical methodology.Using the French National Health Data System, which covers 99% of residents, the authors identified 31,724 patients without a prior diagnosis of pulmonary hypertension exposed to TKIs from January 1, 2008 to December 31, 2024, with a year of stable healthcare coverage.The study employed a prevalent new-user design to strengthen causal inference. 6Patients newly initiating Dasatinib, Nilotinib, Bosutinib, Ponatinib, or Asciminib (collectively referred to as DNBPA) were matched to Imatinib users based on age, calendar year, and duration of Imatinib exposure.Weighting was applied to address differences in patient characteristics that could introduce confounding, which achieved good balance between groups on key characteristics.The primary outcome was incident PAH, defined using electronic health record-based criteria.Before weighting, 47 PAH cases occurred in 6,625 Dasatinib users versus 21 in