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Nusinersen/onasemnogene-abeparvovec Elevated liver enzymes following off-label use and thrombocytopenia: 4 case reports

In a retrospective study of 5 patients with type 1 spinal muscular atrophy (SMA1), 3 girls and 1 boy [exact age at reaction onset not stated] were described, who developed elevated liver enzymes or thrombocytopenia during the combination therapy with nusinersen and onasemnogene-abeparvovec, wherein 2 girls received off-label treatment with onasemnogene-abeparvovec [routes, dosages and duration of treatment to reaction onset not stated]. Patient 1: The girl, at the age of 6 months, had been diagnosed with SMA1. At the age of 7 months, she was started with nusinersen, resulting in improvement of the symptoms. At that time, the physician decided to initiate onasemnogene-abeparvovec [onasemnogene]. Therefore, from the age of 21 months, she started receiving onasemnogene-abeparvovec in the clinical trials managed access program (off-label use) and therapy with nusinersen was continued. However, during the combination treatment, she developed marked increase in liver enzymes manifesting as hepatic dysfunction. Therefore, she was initiated with prednisolone treatment. Subsequently, her liver enzyme normalised. Hence, the dose of prednisolone was gradually tapered and discontinued at the age of 27 months. Patient 2: The girl, at the age of 1 month, had been diagnosed with SMA1. At the age of 1.5 months, she was started with nusinersen, resulting in improvement of the symptoms. At that time, the physician decided to initiate onasemnogene-abeparvovec [onasemnogene]. Therefore, from the age of 18 months, she started receiving onasemnogene-abeparvovec in the clinical trials managed access program (off-label use) and therapy with nusinersen was continued. However, during the combination treatment, she developed irritability, scleral icterus, hepatomegaly with marked increased elevated liver enzymes (hepatic dysfunction). Therefore, she was initiated with prednisolone treatment. Subsequently, she was hospitalised and liver biopsy was performed. Based on sign and symptoms, liver failure was suggested. However, her liver enzyme normalised with prednisolone therapy. Hence, the dose of prednisolone was gradually tapered and discontinued at the age of 25 months. Patient 4: The boy, at the age of 6 months, had been diagnosed with SMA1. At the age of 6.5 months, he was started with nusinersen, resulting in improvement of the symptoms. At that time, the physician decided to initiate onasemnogene-abeparvovec [onasemnogene]. Therefore, from the age of 23 months, he started receiving onasemnogene-abeparvovec therapy and therapy with nusinersen was continued. However, during the combination treatment, he developed transient thrombocytopenia and mild increased in liver enzymes manifesting as hepatic dysfunction. Therefore, he was initiated with prednisolone treatment. Subsequently, his liver enzyme normalised. Hence, the dose of prednisolone was gradually tapered and discontinued at the age of 27 months. Patient 5: Th