Characteristics and outcomes of gemcitabine-associated pulmonary hypertension

<bold>Background:</bold> Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. <bold>Objectives:</bold> We aimed to analyze cases of PH or associated symptoms reported with gemcitabine usage in the French and World Health Organization's (WHO) pharmacovigilance database. <bold>Methods:</bold> We identified incident cases of precapillary PH confirmed by right heart catheterization in patients treated with gemcitabine from the French PH Registry between January 2007 to December 2022. A pharmacovigilance disproportionality analysis was conducted using the WHO pharmacovigilance database. <bold>Results:</bold> We identified nine cases of PAH, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (min-max 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L/min/m², and pulmonary vascular resistance of 6.3 (3.1-12.6) WU. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Importantly 6/9 patients had a clinical improvement on withdrawal of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine, which was the only suspected antineoplastic drug in 55 cases. <bold>Conclusion:</bold> Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH.