Allergic Reactions With Intravenous Compared With Intramuscular Pegaspargase in Children With High-risk Acute Lymphoblastic Leukemia: A Population-based Study From the Maritimes, Canada

Abstract

Intravenous (IV) administration of pegaspargase in children with acute lymphoblastic leukemia (ALL) may be associated with an increased risk of allergic reactions, and thus the need for more costly intramuscular (IM) erwinia asparaginase. In 128 patients allergic reactions were documented in 3% and 14% of those who received IM and IV pegaspargase, respectively (P=0.029). These reactions were primarily contributed to by high risk (HR)-ALL patients (P<0.01). The possible decreased efficacy and quality of life and the substantial costs entailed by switching from IV pegaspargase to IM erwinia should prompt reconsideration of the IV administration route for pegaspargase in HR-ALL patients.

Universal premedication and therapeutic drug monitoring for asparaginase‐based therapy prevents infusion‐associated acute adverse events and drug substitutions

“…As foreign proteins, all asparaginase products are associated with systemic clinical hypersensitivity reactions, manifested on the spectrum of urticaria, bronchospasm, angioedema, or anaphylaxis . The incidence of hypersensitivity varies widely based on form, routes, frequency, etc., but is usually estimated at 10% to 30% . These clinical reactions have been shown to be strongly associated with the production of neutralizing antibodies and lack of asparaginase activity, although the severity of the reaction does not correlate with the risk of neutralization.…”

“…These clinical reactions have been shown to be strongly associated with the production of neutralizing antibodies and lack of asparaginase activity, although the severity of the reaction does not correlate with the risk of neutralization. In fact, there are patients who develop neutralizing antibodies without any clinical manifestations, which is known as “silent inactivation.” Historically, the incidence of silent inactivation with IV PEG was relatively high at 8% to 15%, especially compared with the rates seen with the IM formulations (3%), although this was in the setting of IV PEG being used following native E. coli l ‐asparaginase . Therefore, given this potentially high incidence as well as the inability to perform therapeutic drug monitoring (TDM), premedication with histamine antagonists or steroids has generally been avoided, for fear of “masking” this clinical reaction as the sole indicator of potential neutralization.…”

“…With the almost universal adoption of IV PEG as the standard formulation in ALL from the beginning of treatment, two important facts have become clear. First, when it is used beginning in induction, the rate of silent inactivation with IV PEG is much lower than with other formulations, with 0% to 3% incidence . Second, with the use of IV PEG, a distinct type of acute clinical reaction (a nonallergic infusion reaction) is becoming increasingly recognized in addition to antibody‐producing hypersensitivity reactions.…”

Reply to: Comment on: Comparison of hypersensitivity rates to intravenous and intramuscular PEG‐asparaginase in children with acute lymphoblastic leukemia: A meta‐analysis and systematic review

“…In the light of the evidence presented by Dholaria and colleagues, we performed an update of our meta-analysis using the same methods outlined in our manuscript. 2 We identified six additional reports, two of which were referenced by Dholaria and colleagues, 3,4 all of which were deemed unfit for inclusion in our meta-analysis for the following reasons: Data was already included in our meta-analysis from an abstract which is now formally published, 5 inclusion of relapsed patients 6 or young adults, 4,7 insufficient data reported to conduct meta-analysis (i.e., only grades 3-4 hypersensitivity reactions reported) 4,7,8 and both study arms did not use pegylated asparaginase. 3 We, therefore, performed a meta-analysis without 5,[9][10][11] and with 1,5,[9][10][11] the data reported by Dholaria and colleagues, which is presented in Figure 1, to calculate the absolute risk difference of IV versus IM.…”

“…2 We identified six additional reports, two of which were referenced by Dholaria and colleagues, 3,4 all of which were deemed unfit for inclusion in our meta-analysis for the following reasons: Data was already included in our meta-analysis from an abstract which is now formally published, 5 inclusion of relapsed patients 6 or young adults, 4,7 insufficient data reported to conduct meta-analysis (i.e., only grades 3-4 hypersensitivity reactions reported) 4,7,8 and both study arms did not use pegylated asparaginase. 3 We, therefore, performed a meta-analysis without 5,[9][10][11] and with 1,5,[9][10][11] the data reported by Dholaria and colleagues, which is presented in Figure 1, to calculate the absolute risk difference of IV versus IM. Our analysis reveals that inclusion of the findings by Dholaria and colleagues marginally shifted the absolute risk difference from 0.12 (95% CI 0.06-0.18) to 0.11 (95% CI 0.06-0.16) and remained significant.…”