Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase

Abstract

Purpose: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase.

Patients and methods: The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy.

Results: Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients.

Conclusions: These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.

Figure 1. Asparaginase dosing schedule of patients challenged with native E. coli. asparaginase

Two pediatric ALL patients were challenged with native E. coli asparaginase (Elspar) after hypersensitivity reactions to PEGylated E. coli asparaginase (Oncaspar) and Erwinia asparaginase (Erwinase). Planned Oncaspar (), Erwinia (), and Elspar (△) doses relative to the start of induction treatment are shown for Patient A (A) and Patient B (B). All doses that were tolerated by the patients are indicated by filled symbols (, , and ▲), and asparaginase doses that induced hypersensitivity reactions are illustrated in red ( and ). The treatment phases included along the x-axis are induction, consolidation, continuation weeks 1-6 (cont W1-6), reinduction I (Re I), continuation weeks 10-16 (cont W10-16), reinduction II (Re II), and continuation weeks 20-29 (cont W20-29). Therapy for Patient A was interrupted during reinduction II due to severe pancreatitis.

Figure 2. Asparaginase activity modeling for pharmacokinetic parameter estimation

The asparaginase activity of samples collected during continuation treatment from two pediatric ALL patients challenged with native E. coli asparaginase (Elspar) was measured (○) and modeled using a one-compartment pharmacokinetic model with first-order absorption and Michaelis-Menten elimination. The solid black line represents the best fit from the pharmacokinetic modeling and the solid red line indicates the 0.1 IU/mL serum concentration threshold required for efficient asparagine depletion.