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

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/m2/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. Pediatr Blood Cancer 2015.

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

“…[22] In studies of asparaginase Erwinia chrysanthemi (25,000 IU/m 2 ), 96% and 83% of patients showed asparaginase activity levels >0.1 IU/mL 48 h following IM or IV administration, respectively. [24,25] Figure 1. Simulation of serum asparaginase activity following repeated administration of intravenous (IV) and intramuscular (IM) asparaginase Erwinia chrysanthemi in two example patients.…”

“…[44,45] Within the last 15 years, reported rates of hypersensitivity in clinical trials have varied across studies using different routes of administration and asparaginases (Table 2). [14,[23][24][25]34,38,42,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Recently, a number of retrospective reports have compared the incidence of hypersensitivity between IV and IM PEG-asparaginase (Table 3). [8,34,[60][61][62][63][64] In a pediatric study of 318 patients, Petersen et al reported a 9% greater incidence of hypersensitivity following IV administration of PEG-asparaginase compared with IM PEG-asparaginase (p ¼ .028).…”

Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation

“…12,35 Although IM administration has largely been utilized in the United States, Erwinia asparaginase is now approved for IV use as well. 37 The optimal dose, schedule, and route of Erwinia asparaginase, however, remain unclear and are worthy of further investigation. Large inter-individual differences in clearance underscore the importance of individualized dosing schedules based on asparaginase activity.…”

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

“…While different forms of the drug offer multiple options for patients who experience allergic reactions, all forms are associated with metabolic complications that are difficult to predict, yet intensify with age (1,2,13,16,22,28,31,50,52,62).…”