Proteasome inhibitor-associated thrombotic microangiopathy: a real-world retrospective and pharmacovigilance database analysis.

OBJECTIVES

Thrombotic microangiopathy (TMA) is associated with carfilzomib, but the potential association between bortezomib or ixazomib exposure and TMA is still unknown. Besides, the knowledge of carfilzomib-induced TMA is based mainly on case reports. We aim to quantify the risk and better characterize the clinical features of proteasome inhibitor (PI)-induced TMA.

METHODS

Data from 2004 to 2023 on TMA events induced by PIs were retrieved from the FDA Adverse Event Reporting System (FAERS) database and conducted disproportionality analyse. Case reports/series from 2004 to 2023 on PI-induced TMA were extracted and analyzed retrospectively.

RESULTS

FAERS pharmacovigilance data identified 225 TMA cases across 213 individuals related to PIs therapy. PIs were significantly associated with TMA (n = 213, ROR 1.71 [1.49-1.96]; EBGM 1.70 [1.52]), and carfilzomib had the greatest proportion (58.7%) and highest positive signal values (n = 125, ROR 17.97 [15.04-21.47]; EBGM 17.49 [15.07]) of TMA. Sixty cases (median age: 63 years) from 35 studies showed evidence of TMA, with 37 (61.7%) were male. The typical initial symptoms were gastrointestinal symptoms (45.3%), fever (24.5%), fatigue/asthenia (20.8%), neurological signs (18.9%), and dyspnea (17.0%). The median time to TMA onset was 8 days. Most patients presented with hemolytic anemia (98.1%), thrombocytopenia (96.6%), and acute kidney injury (96.7%). Cessation of PIs and treatment with plasma exchange therapy (25.0%), hemodialysis (31.7%), and eculizumab (26.7%) were associated with improved hematologic outcomes (96.3%) and renal outcomes (93.3%).

CONCLUSION

This study identified PIs agents with significant reporting associations with TMA. A prompt diagnosis of TMA and supportive treatments are necessary for patients receiving PIs concurrent with anemia, thrombocytopenia, and acute kidney injury.