A Pilot Study to Describe Symptomatic Hyperammonemia Secondary to Recombinant Erwinia Asparaginase

Asparaginase therapy is essential for the treatment of pediatric acute lymphoblastic leukemia/lymphoma (ALL/LLy). For patients who develop hypersensitivity to a first-line Escherichia coli (E. coli)-derived product, the standard of care is to transition to an Erwinia-derived product. Given that all asparaginase products 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.

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. Additional objectives included identifying potential risk factors for symptomatic hyperammonemia.

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 treated by the pediatric hematology/oncology team at our institution who were receiving recombinant Erwinia asparaginase were eligible. Patients were excluded if they were less than 1 year of age 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 h or 72 h after the previous dose.

Five patients were included, three of whom were male (60%). Three patients had T-cell ALL (60%), one patient had B-cell ALL (20%), and one patient had infantile B-cell ALL (20%). The median age was 5 years (range 1-14). Two patients were followed for two courses of recombinant Erwinia asparaginase, and the remaining patients were followed for a single course. Median baseline plasma ammonia level was 12 μmol/L. Median ammonia level while receiving recombinant Erwinia asparaginase was 146 μmol/L. Three patients (60%) developed symptomatic hyperammonemia with a median ammonia level of 174 μmol/L (range 108-343). The reported symptoms were nausea (100%), fatigue (66.7%), and decreased appetite (33.3%). The remaining two patients experienced asymptomatic hyperammonemia with a median ammonia level of 125 μmol/L (range 55-304).

Based on our small cohort, symptomatic hyperammonemia may be a common adverse effect for patients receiving recombinant Erwinia asparaginase. Evaluating plasma ammonia levels appears reasonable in patients who are experiencing nausea or other symptoms of hyperammonemia. Additional studies are warranted to further characterize this toxicity.