Management of acute liver toxicity after delandistrogene-moxeparvovec with the use of steroid sparing agents

Topic:

Clinical Management

Poster Number: P42

Author(s):

Carmen Astudillo Leon, MD, University of Florida, Renata Shih, MD, University of Florida, Carla Zingariello, DO, University of Florida, Christina Chadwick, MD, University of Florida, Renee Modica, MD, University of Florida, Lawrence Shoemaker, MD, University of Florida, Stephanie Salabarria, BS, University of Florida, Gina Killian, DNP, APRN, University of Florida, Jennifer Shifflet, PA-C, University of Florida, Julie Berthy, DNP, University of Florida, Barry Byrne, MD, PhD, University of Florida

A 5-year-old Non-Hispanic White male with Duchenne muscular dystrophy (Deletion 45-50, 21Kg), received delandistrogene-moxeparvovec following immunosuppression with prednisolone. He developed a progressive increase in transaminases (alanine aminotransferase, ALT, aspartate aminotransferase, AST), and gamma-glutamyl transferase (GGT) first detected on day 45 post dosing: GGT 116 U/L, (ULN: 61, Baseline: 8U/L), ALT 891 IU/L (baseline: 423 IU/L), AST 721 IU/L (baseline:188 IU/L), while on additional prednisolone (total dose 1.75mg/kg/d). Total prednisolone was increased to 57mg PO (2.75mg/kg/d) for 5 days without improvement (ALT: 814 IU/L AST: 1054 IU/L, GGT: 123 U/L Total bili: 0.5mg/dL). Intravenous (IV) methylprednisolone was given on days 49, 51 (2mg/kg each), day 53 (10mg/kg), all while receiving 2.75mg/kg/d PO. Patient was hospitalized from day 54 to 59 for close monitoring and initiation of sirolimus as GGT increased to 189 U/L. He received 2mg/kg/d of methylprednisolone and sirolimus at a loading dose of 3mg/m2, and transitioned to a maintenance dose of 1mg/m2. Further work up revealed normal liver ultrasonographic features and ruled out other acute infectious etiologies. He remained clinically asymptomatic. His GGT peaked at 210 U/L on Day 56 (AST 825 IU/L, ALT 1109 IU/L), and progressively declined afterwards. He was discharged on 2mg/kg oral prednisolone and sirolimus. Sirolimus trough was maintained within a goal of 4-6. On day 86, GGT was below the ULN 60 U/L, and additional steroids were tapered over two weeks. Sirolimus was continued for 3months, without GGT rebound after discontinuation.
Discussion: Acute liver injury related to adeno-associated virus gene therapy has been described. Although in some cases, liver abnormalities resolve without intervention, many require high doses of steroids. Interestingly, our patient did not improve after intravenous steroids and required alternative approaches targeting T cell response. Sirolimus has been used in preclinical models and previous clinical trials. This approach allowed the treatment of a steroid resistant liver injury and decreased the use of prolonged high doses of steroids, which can result in detrimental short- and long-term effects. Gene therapy centers should consider the use of steroid sparing agents when treating acute liver injury, particularly when there is a poor response to steroids.