Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli-Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia

Lynda M Vrooman, Ivan I Kirov, ZoAnn E Dreyer, Michael Kelly, Nobuko Hijiya, Patrick Brown, Richard A Drachtman, Yoav H Messinger, A Kim Ritchey, Gregory A Hale, Kelly Maloney, Yuan Lu, Paul V Plourde, Lewis B Silverman, Lynda M Vrooman, Ivan I Kirov, ZoAnn E Dreyer, Michael Kelly, Nobuko Hijiya, Patrick Brown, Richard A Drachtman, Yoav H Messinger, A Kim Ritchey, Gregory A Hale, Kelly Maloney, Yuan Lu, Paul V Plourde, Lewis B Silverman

Abstract

Background: Erwinia asparaginase is antigenically distinct from E.coli-derived asparaginase and may be used after E.coli-derived asparaginase hypersensitivity. In a single-arm, multicenter study, we evaluated nadir serum asparaginase activity (NSAA) and toxicity with intravenously administered asparaginase Erwinia chrysanthemi (IV-Erwinia) in children and adolescents with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma with hypersensitivity to E.coli-derived asparaginase.

Patients and methods: Between 2012 and 2013, 30 patients (age 1-17 years) enrolled from 10 centers. Patients received IV-Erwinia, 25,000 IU/m(2)/dose on Monday/Wednesday/Friday, for 2 consecutive-weeks (6 doses = 1 cycle) for each dose of pegaspargase remaining in the original treatment plan. The primary objective was to determine the proportion of patients achieving NSAA ≥ 0.1 IU/ml 48 hr after dose 5 in Cycle 1. Secondary objectives included determining the proportion achieving NSAA ≥ 0.1 IU/ml 72 hr after Cycle 1 dose 6, and the frequency of asparaginase-related toxicities.

Results: Twenty-six patients completed Cycle 1; 24 were evaluable for NSAA assessment. In Cycle 1, NSAA ≥ 0.10 IU/ml was detected in 83% of patients (95% confidence interval [CI], 63-95%) 48 hr post-dose 5 (mean ± SD; 0.32 IU/ml ± 0.23), and in 43% (95% CI, 22-66%) 72 hr post-dose 6 (mean ± SD; 0.089 IU/ml ± 0.072). For all 30 patients over all cycles, hypersensitivity/infusional reactions with IV-Erwinia occurred in 37%, pancreatitis 7%, and thrombosis 3%.

Conclusions: IV-Erwinia administration in children/adolescents appeared feasible and tolerable. A therapeutically-effective NSAA (≥ 0.10 IU/ml) was achieved in most patients at 48 hr, but in fewer than half 72 hr post-dosing, suggesting that monitoring NSAA levels and/or every 48 hr dosing may be indicated.

Trial registration: ClinicalTrials.gov NCT01643408.

Keywords: Erwinia asparaginase; acute lymphoblastic leukemia; childhood ALL; clinical trials; pharmacokinetics.

© 2015 Wiley Periodicals, Inc.

Figures

Figure 1
Figure 1
Patients evaluable for primary nadir serum asparaginase activity (NSAA) analysis. *Sample obtained outside the protocol‐specified time‐frame.

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