Characteristics and outcomes of patients developing pulmonary hypertension associated with proteasome inhibitors.

Abstract

Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PI). To evaluate the association between PI and PAH. Characteristics of incident PAH cases previously treated with Carfilzomib or Bortezomib were analyzed from the French PH Registry and the VIGIAPATH program from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the WHO's global database, and a meta-analysis of randomized controlled trials. Eleven incident cases of PI associated PAH were identified (6 with Carfilzomib and 5 with Bortezomib) with a female: male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (2 from right heart failure, 1 from respiratory distress, and 1 from an unknown cause). At diagnosis, 6 were in NYHA-Fc III/IV with severe hemodynamic impairment (median mean pulmonary artery pressure of 39 mmHg, cardiac index 2.45 L/min·m-2, and pulmonary vascular resistance of 7.2 WU). In the WHO pharmacovigilance database, 166 cases of PH associated with PI were reported since 2013 with significant statistics of disproportionate reporting (SDR) for Carfilzomib, regardless of the definition of cases or control group. However, SDR for Bortezomib was inconsistent. The systematic review identified 17 clinical trials, and Carfilzomib was associated with a significantly higher risk of dyspnea, severe dyspnea and PH compared to Bortezomib. PI may induce PAH in patients undergoing treatment, with Carfilzomib emitting a stronger signal than Bortezomib, and these patients should be monitored closely.