Biopsy-proven immune-mediated hepatitis after valoctocogene roxaparvovec

Abstract

Background and Aims: Valoctogene roxaparvovec is an approved and efficacious gene therapy (GT) for severe hemophilia A (HA), however alanine aminotransferase (ALT) elevation after dosing raises safety concerns. Corticosteroids are the first-line therapy for ALT>1.5X the baseline value, but this indication requires further pathological characterization in humans. We explored mechanisms of ALT elevation to personalize corticosteroid therapy. Methods: Follow-up data on real-life experience with valoctogene roxaparvovec were collected. Transjugular liver biopsy for histology, transmission electron microscopy and immunophenotype characterization were compared with positive/negative controls. Results: Five severe HA patients were treated with valoctogene roxaparvovec. Four (80%) had ALT>1.5X the baseline value but two had transaminase above the normal range (59 U/L) and lowering of transgene expression and were treated with prednisone. Liver biopsy from these two cases before starting prednisone revealed acute immunemediated hepatitis and abnormal enlargement of the smooth endoplasmic reticulum of hepatocytes. ALT normalized along with preservation of transgene expression after a personalized schedule of oral prednisone. High T-cytotoxic and low T-regulatory activity was observed during acute hepatitis. The median transgene expression at the end of the follow-up was 83(12-206)% (chromogenic assay), but it was highly variable regardless the exposure to prednisone: 48(12-83)% in patients treated with prednisone and 194(20-206)% in patients not treated with prednisone. Conclusions: Immune-mediated hepatitis can cause ALT elevations in HA after valoctogene roxaparvovec and, in selected cases, a biopsy-proven diagnosis could support a safer and more effective therapeutic course of prednisone to maintain optimal transgene expression.