Pilot Study to Establish Incidence and Characteristics of Patients at Risk for Symptomatic Hyperammonemia Secondary to Recombinant Erwinia Asparaginase

Presenting Authors: Catherine Martin, PharmD, and Alexis Kuhn, PharmD, BCOP, Mayo Clinic, Rochester, MN

BACKGROUND: Asparaginase therapy is essential for the treatment of pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. For patients who had hypersensitivity to a first-line Escherichia coli–derived drug, the standard of care is to transition to an Erwinia-derived drug. All asparaginase drugs exert their antileukemic effects by enzymatically breaking down asparagine to aspartic acid and ammonia. Elevations in ammonia levels are anticipated during asparaginase treatment; however, symptomatic hyperammonemia is not expected. Recombinant Erwinia asparaginase is relatively new to the market, and there have been several case reports of symptomatic hyperammonemia with this specific formulation.

OBJECTIVES: The primary objective of this prospective study was to establish the incidence of symptomatic hyperammonemia secondary to recombinant Erwinia asparaginase and to determine if a larger multicenter trial was warranted. An additional objective was to identify the potential risk factors for symptomatic hyperammonemia.

METHODS: This single-center, prospective trial received institutional review board approval. Funding was provided by the Mayo Clinic Clinical and Translational Science Award (grant number: UL1TR002377) and the Mayo Clinic Department of Pharmacy. All patients who received treatment by the pediatric hematology/oncology team at our institution who were receiving recombinant Erwinia asparaginase were eligible for the study. Patients were excluded if they were aged <1 year at study entry. Enrolled participants had a baseline plasma ammonia level obtained, followed by twice-weekly ammonia levels while receiving recombinant Erwinia asparaginase. Aside from baseline, all ammonia levels were trough levels measured either 48 or 72 hours after the previous dose.

RESULTS: A total of 5 patients were included, 3 of whom were male (60%). In all, 3 patients had T-cell ALL (60%), 1 patient had B-cell ALL (20%), and 1 patient had infantile B-cell ALL (20%). The median age was 5 years (range, 1-14 years). A total of 2 patients were followed for 2 courses of recombinant Erwinia asparaginase, and the remaining patients were followed for a single course. The mean baseline plasma ammonia level was 14.4 mcmol/L. The mean ammonia level while receiving recombinant Erwinia asparaginase was 157.5 mcmol/L. In all, 3 (60%) patients had symptomatic hyperammonemia with a mean ammonia level of 234.8 mcmol/L (range, 212-343 mcmol/L). The patients’ symptoms included nausea (100%), fatigue (66.7%), and decreased appetite (33.3%). All 3 patients who developed symptoms were men and had T-cell ALL. The remaining 2 patients had asymptomatic hyperammonemia with a mean ammonia level of 122.2 mcmol/L (range, 55-304 mcmol/L).

CONCLUSION: Based on our small cohort, symptomatic hyperammonemia may be a common adverse event for patients receiving recombinant Erwinia asparaginase. Checking plasma ammonia levels is reasonable in patients who have nausea and vomiting.

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