Anaphylaxis Associated with Calaspargase in Pediatric Patients with Acute Lymphoblastic Leukemia

Background: Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in the pediatric population. The current standard of care for pediatric ALL involves multi-agent chemotherapy regimen leading to a 5-year overall survival of more than 90%. Asparaginase is a key component of treatment for ALL as the leukemia cells lack asparagine synthetase making them dependent on extracellular asparagine for cell growth. There have been different types of asparaginase products used in clinical trials over the years including Native or L-asparaginase, Erwinia asparaginase, Pegaspargase (PEG) and Calaspargase pegol-mknl (Cal-PEG). Cal-PEG was approved in December 2018 by the Food and Drug Administration for ALL in pediatric and young adult patients ages 1 month to 21 years. The distribution of PEG was ceased in December 2022 making Cal-PEG as the sole product for children and young adults less than 21.5 years of age. Asparaginase products are bacterial derivatives so the various forms have been associated with hypersensitivity and anaphylaxis. There are anecdotal reports of increased rates of hypersensitivity and anaphylaxis with Cal-PEG. Our aim was to confirm this observation and compare the anaphylaxis rates and the associated healthcare burden along with other toxicities between the two forms of asparaginase - PEG and Cal-PEG.

Methods: We performed a retrospective study using a de-identified database with 93 contributing health care organizations within the United States (TriNetX). We identified all patients between the ages of 1-21 years with a diagnosis of ALL (ICD-10: C91.0) from 2010-2024. Patients were then categorized into two cohorts, based on whether they received Cal-PEG or PEG. We performed 1:1 propensity score matching, based on patient demographics and baseline clinical data. Independent t-tests were performed for continuous data and chi-square tests for categorical data. We evaluated differences in outcome risk using odds ratios and 95% confidence intervals. All tests were two-tailed with an alpha level of .05.

Results: Of the 67,030 patients with a diagnosis of ALL in the database, 4139 patients met criteria to be included in the study. 3800 patients (91.8%) received PEG and 339 patients (8.2%) received Cal-PEG. Patients receiving Cal-PEG were more likely to have a diagnosis of anaphylaxis (2.9 vs 0.7%; OR 4.59, p<0.001), receive Epinephrine (35.5 vs 17.7%; OR 2.55, p <0.001) and had more admissions to the ICU (2.9 vs 1.7%; OR 1.75, p=0.101). Patients receiving Cal-PEG were also more associated with Fibrinogen repletion (2.9 vs 0.3%; OR 11.2, p<0.001) and Anti-thrombin repletion (2.9 vs 1.5%; OR 2.03, p=0.038). Among all the toxicities related to asparaginase products, venous thrombosis (7.7 vs 12.2%; OR 0.6, p=0.013) and hemorrhage (2.9 vs 11.6 %; OR 0.23, p<0.001) were less associated with Cal-PEG whereas pancreatitis, pulmonary embolism and hepatic veno-occlusive disease were not different between the two groups.

Conclusions: In our large nationwide sample, Cal-PEG was associated with increased anaphylaxis as compared to PEG in pediatric and young adult patients with ALL, and led to increased healthcare burden. Venous thrombosis and hemorrhage were less associated with Cal-PEG, even though other toxicities remained the same between the two types of asparaginase. Anaphylaxis rates need to be prospectively confirmed in Children's Oncology Group studies, so that preventive strategy guidelines can be developed for these patients.

Ahuja:Governor's Office, State of Ohio: Other: Membership on Rare Disease Advisory Council for the State of Ohio; US FDA: Honoraria, Other: Member of the Blood Products Advisory Committee; Case Western Reserve University: Patents & Royalties: Patent for US 11,408,844 issued; XaTek: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioMarin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.