Safety profile of asparaginase Erwinia chrysanthemi in a large compassionate‐use trial

Abstract

Background L‐Asparaginase is an integral component of standard chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Clinical hypersensitivity, a common reason for treatment discontinuation, has been reported in 10–30% of patients receiving Escherichia coli‐derived asparaginase. After hypersensitivity, E. coli‐derived asparaginase should be discontinued and an alternative asparaginase preparation, such as asparaginase Erwinia chrysanthemi, may be initiated. We conducted a compassionate‐use study to collect additional safety information on asparaginase Erwinia chrysanthemi and to support FDA approval of the product. Procedure Patients with ALL or lymphoblastic lymphoma (LBL; N = 1368) who developed a hypersensitivity reaction (grade ≥2) to an E. coli‐derived asparaginase participated in this trial. The recommended asparaginase Erwinia chrysanthemi dose was 25,000 IU/m2 three days per week (Monday/Wednesday/Friday) for two consecutive weeks for each missed pegylated E. coli‐derived asparaginase dose and 25,000 IU/m2 for each missed nonpegylated asparaginase dose for the completion of their planned asparaginase treatment. Results Adverse event reports and/or case report forms were completed for 940 patients. The most common adverse event (AE) was hypersensitivity (13.6%). Eighteen patients (1.9%) died during the study. Most patients (77.6%) completed their planned asparaginase treatment with asparaginase Erwinia chrysanthemi. There was no apparent difference in the incidence of the most commonly reported AEs with asparaginase treatment by age, administration, or disease state. Conclusions This study further established the safety profile of asparaginase Erwinia chrysanthemi in patients with ALL or LBL who had a hypersensitivity reaction to an E. coli‐derived asparaginase. Pediatr Blood Cancer 2014;61:1232–1238. © 2014 Wiley Periodicals, Inc.

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

“…[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).…”

IV Administration of Erwinia-Derived Asparaginase in Pediatric Patients with Acute Lymphoblastic Leukemia: Single-Centre Case Series

“…2,7,13 In a review of 1368 patients who experienced hypersensitivity to E. coli-derived asparaginase and subsequently were switched to EA, a subgroup analysis comparing IV and IM administration suggested a trend for increased incidence of hypersensitivity reactions and hyperglycemia with the IV route (17.2% versus 11.7% and 6.9% versus 3.8%, respectively). 7 At the LHSC Children's Hospital, all patients are asked about possible symptoms of hyperglycemia, such as polydipsia and polyuria, and biochemical laboratory markers such as bilirubin and transaminases are monitored periodically for evidence of hepatic dysfunction. Notably, measured laboratory values remained within normal ranges throughout treatment for most of the patients in this case series.…”

“…3 A large multicentre trial established the safety profile of EA in children with acute lymphoblastic leukemia or lymphoblastic lymphoma who had prior hypersensitivity reactions to E.coli-derived asparaginase products. 7 Substitution of EA into treatment regimens is critical to allow completion of planned asparaginase therapy. Importantly, decreased exposure to asparaginase because of intolerance has been associated with inferior outcomes in pediatric acute lymphoblastic leukemia.…”

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

“…The incidence of hypersensitivity is variable depending on three different formulations of L-ASP used in clinical practice, with rates that vary from 20% to 31.5% in native E. coli-treated patients [23][24][25], from 1.8% to 9.4% in PEG-treated patients [26][27][28], and from 10.9% to 33% [29][30][31] in Erwinia-treated patients. Typically, patients exhibiting clinical allergy symptoms to one formulation of asparaginase are switched to another product to ensure they receive the most efficacious treatment regimen possible [22,32].…”