Allergic reactions and antiasparaginase antibodies in children with high‐risk acute lymphoblastic leukemia: A children's oncology group report

Abstract

Purpose To assess the incidence of clinical allergy and end-Induction anti-asparaginase antibodies in children with high-risk acute lymphoblastic leukemia treated with pegylated E. coli asparaginase (PEG ASNase) and determine if they carry any prognostic significance. Patients and Methods Of 2057 eligible patients, 1155 patients were allocated to “augmented” arms where PEG ASNase replaced native ASNase post-Induction. Erwinia ASNase could replace native ASNase after allergy, if available. Allergy and survival data were complete for 990 patients. End-Induction antibody titers were available for 600 patients. Results During Consolidation, 29.2% (289/990 patients) had an allergic reaction. There were less allergic reactions to Erwinia ASNase than native ASNase (OR=4.33; p<0.0001) or PEG ASNase (OR=3.08; p<0.0001) during Interim Maintenance #1 only. There was no significant difference in 5-year EFS between patients who received PEG ASNase throughout the entire study post-Induction versus those who developed an allergic reaction to PEG ASNase during Consolidation and received Erwinia ASNase subsequently (80.8 ± 2.8% and 81.6 ± 3.8% (p=0.66), respectively). Patients with positive antibody titers post-Induction were more likely to have an allergic reaction to PEG ASNase (OR=2.4; p<0.001). Neither the 5-year EFS between patients with a negative versus positive antibody titer (80 ± 2.6% and 77.7 ± 4.3%, respectively, p=0.68) nor patients who did not receive any asparaginase post-Consolidation and patients who received PEG ASNase throughout the study (p=0.22) were significantly different. Conclusion We demonstrate differences in the incidence rates of toxicity between asparaginase preparations, but not in EFS. The presence of anti-asparaginase antibodies did not affect EFS.

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

“…Because pegylated asparaginase becomes inactivated in virtually all patients with an allergic reaction irrespective of its severity, 9 any degree of hypersensitivity should logically lead to a change from Escherichia coli-derived pegylated asparaginase to Erwinia chrysanthemi-derived asparaginase. 10 In addition to the defi nition of asparaginase hypersensitivity, the PTWG defi ned silent inactivation in patients without clinical allergy as trough asparaginase activity levels less than the lower level of quantifi cation (LLQ; preferably measured in two independent samples)-ie, a day 7 asparaginase activity level of less than 100 international units per L or a day 14 level of less than LLQ in case of biweekly pegylated asparaginase, or both; and a 48 h post-dose level of less than LLQ in case of E chrysanthemi-derived asparaginase (given two to three times a week).…”

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

“…[68,71] Asparaginase Erwinia chrysanthemi has shown limited cross reactivity with antibodies formed in patients treated with E. coli-derived asparaginase and can therefore successfully achieve therapeutic activity levels and maintain clinical outcomes in patients with hypersensitivity to PEG-asparaginase. [24,43,50,72] In clinical trials, 76-78% of patients who experienced previous hypersensitivity (grade !2) to an E. coli-derived asparaginase were able to complete their full asparaginase treatment regimen with asparaginase Erwinia chrysanthemi. [24,30] Due to differences in pharmacokinetics, the dosing frequency must be increased in patients who switch to asparaginase Erwinia chrysanthemi to achieve appropriate therapeutic activity.…”

Immunogenicity assessment of fungal l-asparaginases: an in silico approach

“…l-asparaginase (ASNase) is considered a key therapeutic enzyme for the treatment of acute lymphoblastic leukemia (ALL) nowadays. This disease is recognized as the most frequent cancer among children [1], also affecting adults [2]. ALL consists of the overproduction of undifferentiated lymphocytes in the bone marrow, which can lead to death [3].…”