Adverse Hepatobiliary Effects of Pegaspargase: Diagnostic Features and Potential Treatment

Abstract

Introduction: Pegaspargase is frequently used to treat patients with B-cell acute lymphoblastic leukemia (B-ALL). Hepatotoxicity is a potential adverse effect. We describe 3 cases of suspected pegaspargase-associated hepatotoxicity and effects of treatment.Figure: Liver biopsy histology demonstrating features of cholestatic hepatitis, including cholestasis (arrow) and feathery degeneration of hepatocytes (arrowhead) in a background of bile ductular proliferation, acute cholangitis, and microvesicular and macrovesicular steatosis (H&E, 200X).Case Description: Case 1: A 45-year-old man with relapsing B-ALL was treated with chemotherapy including pegaspargase. ALT rose from 154 to 626 U/L and total bilirubin (TB) from 0.9 to 21.6 mg/dL, despite ursodiol. Right upper quadrant abdominal ultrasound showed interval hepatic steatosis, compared to CT abdomen 3 months prior. Liver biopsy showed marked steatosis, cholestasis, and hepatocellular degeneration without fibrosis. After 1 month of daily oral vitamin B complex, ALT improved to 73 with TB of 1.1 mg/dL. Case 2: A 41-year-old man with relapsing B-ALL and hepatic graft-versus-host-disease (managed with steroids), was treated with chemotherapy including pegaspargase and methotrexate. ALT rose from 52 to 163 U/L, and TB rose from 0.6 to 23.5 mg/dL despite ursodiol. After 6 days of intravenous (IV) levocarnitine and 1.5 months of oral vitamin B complex, ALT improved to 45 U/L and TB to 2.1 mg/dL. Case 3: A 24-year-old woman with pre-B-ALL who previously underwent stem cell transplants was evaluated for relapse. She was treated with chemotherapy including pegaspargase. Total parenteral nutrition (TPN) was provided for nutrition. After pegaspargase treatment, ALT rose from 26 to 108 U/L, and TB rose from 0.4 to 13.1 mg/dL despite ursodiol. Abdominal ultrasound demonstrated hepatomegaly. TB improved to 4.3 mg/dL after a week of IV levocarnitine and oral vitamin B complex. Persistent elevation in ALT was attributed to effects of other pharmacologic agents and possibly to TPN. Discussion: Pegaspargase is a form of L-asparaginase used in treatment of B-ALL. Although rarely fatal, pegaspargase may cause hepatic impairment. Via depletion of asparagine pools, it impairs mitochondrial oxidation of fatty acids. Microvesicular and macrovesicular steatosis may result. Exclusion of other hepatotoxic agents is important, as other pharmacologic agents may also contribute to abnormal liver enzymes. Through replenishing substrates important to mitochondrial metabolism, treatment with levocarnitine and vitamin B complex has demonstrated efficacy in case reports. No standard treatment regimen has been defined. Empiric treatment may be beneficial in complex cases if clinical suspicion for the diagnosis is high.