Analysis of the Association Between Hypersensitivity Reactions and Asparaginase Activity Monitoring After Pegaspargase Treatment: A Report of Two Cases

Analysis of the Association Between Hypersensitivity Reactions and Asparaginase Activity Monitoring After Pegaspargase Treatment: A Report of Two Cases | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 4 February 2025 V1 Latest version Share on Analysis of the Association Between Hypersensitivity Reactions and Asparaginase Activity Monitoring After Pegaspargase Treatment: A Report of Two Cases Author : Cui xiaoyu [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173867960.00942662/v1 185 views 97 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract A retrospective analysis was conducted on the clinical data and dynamic monitoring of asparaginase activity in two pediatric patients with high-risk acute lymphoblastic leukemia (ALL) who developed hypersensitivity reactions following pegaspargase (PEG-asp) treatment. Case 1: A 4-year-old male developed lip swelling, abdominal pain, and dyspnea after the fourth dose of PEG-asp, but asparaginase activity remained >100 U/L, suggesting a non-antibody-mediated mechanism. Case 2: A 1-year-old male presented with rash, vomiting, and mucosal edema after the fourth dose, accompanied by a rapid decline in asparaginase activity (<100 U/L from day 7 onward), confirming antibody-mediated hypersensitivity. This report highlights the utility of asparaginase activity monitoring in distinguishing hypersensitivity mechanisms and guiding therapeutic decisions, such as switching enzyme formulations. Introduction Asparaginase (ASNase) is a cornerstone of chemotherapy for pediatric acute lymphoblastic leukemia (ALL), depleting plasma asparagine to inhibit leukemic cell proliferation. Pegaspargase (PEG-asp), a polyethylene glycol-modified formulation, is widely used due to its prolonged half-life and reduced immunogenicity. However, hypersensitivity reactions remain a concern, potentially linked to anti-ASNase antibodies that neutralize enzymatic activity. This study explores the relationship between asparaginase activity dynamics and hypersensitivity mechanisms through two cases of PEG-asp-associated reactions. Case Presentations Case 1 Clinical History A 4-year-old male diagnosed with high-risk ALL (BIII subtype) in 2024 received chemotherapy per the South China Cooperative Group ALL2023 protocol. The first three doses of PEG-asp (2,500 IU/m², intramuscular injection) were well tolerated. Hypersensitivity Reaction and Management One hour after the fourth dose, the patient developed lip swelling, abdominal pain, and dyspnea, which resolved with antihistamines. Asparaginase Activity Monitoring Activity levels remained consistently above the therapeutic threshold (>100 U/L): 310 U/L at 24 hours, 450 U/L at 48 hours, 820 U/L at day 7, 580 U/L at day 14, and 254.1 U/L at day 21. Outcome PEG-asp was discontinued. The patient subsequently underwent CD20 monoclonal antibody therapy and hematopoietic stem cell transplantation without recurrence of hypersensitivity. not-yet-known not-yet-known not-yet-known unknown Case 2 not-yet-known not-yet-known not-yet-known unknown Clinical History A 1-year-old male with high-risk ALL (BIII subtype) received the same chemotherapy regimen as Case 1. The first three PEG-asp doses were uneventful. Hypersensitivity Reaction and Management One hour after the fourth dose, the patient exhibited eyelid/lip swelling, generalized urticarial rash, and vomiting, managed with dexamethasone, epinephrine, and antihistamines. Asparaginase Activity Monitoring Activity declined sharply: 143.51 U/L at 24 hours, 118.67 U/L at 72 hours, 2.16 U/L at day 7, and 0 U/L at day 14, falling below the therapeutic threshold (<100 U/L). Outcome Antibody-mediated hypersensitivity was confirmed. Treatment was switched to Erwinia-derived asparaginase (Erwinase, 10,000 IU/m², administered every other day) to complete therapy. not-yet-known not-yet-known not-yet-known unknown 1. Heterogeneous Mechanisms of Asparaginase Hypersensitivity Hypersensitivity reactions to ASNase involve antibody-mediated and non-antibody-mediated pathways:Antibody-mediated reactions :IgE-dependent immediate hypersensitivity : IgE antibodies trigger mast cell degranulation, releasing histamine and leukotrienes, leading to urticaria, angioedema, or anaphylaxis[1]. Such reactions typically occur within minutes to 2 hours post-dose and correlate with rapid activity decline due to antibody neutralization[2]. Case 2’s clinical and biochemical profile aligns with this mechanism.IgG-mediated delayed hypersensitivity : IgG antibodies form immune complexes, activating complement and accelerating drug clearance[3]. Symptoms (e.g., fever, arthralgia) may emerge days after administration. Non-antibody-mediated reactions :Direct histamine release : ASNase may directly stimulate mast cells, mimicking IgE-mediated reactions without antibody involvement[4]. Case 1’s sustained activity (>100 U/L) supports this hypothesis.Complement activation : Drug-antibody complexes activate complement pathways (C3a, C5a), increasing vascular permeability[5]. Clinical Implications :Antibody-mediated reactions require switching to non-cross-reactive ASNase formulations (e.g., Erwinase)[6].Non-antibody-mediated reactions may allow continued therapy under close monitoring or desensitization protocols[7]. not-yet-known not-yet-known not-yet-known unknown 2. Clinical Value of Asparaginase Activity Monitoring Discriminating reaction types :Activity >100 U/L suggests non-antibody mechanisms, preserving therapeutic efficacy[8].Activity <100 U/L indicates antibody-mediated neutralization, necessitating therapeutic adjustments[9]. Guiding formulation switches :Erwinase, with distinct antigenic epitopes, minimizes cross-reactivity risks[10].Post-switch activity monitoring ensures therapeutic efficacy (>100 U/L)[11]. Personalized dosing : Identifies rapid metabolizers (e.g., Case 2) requiring dose adjustments[12]. 3. Pegaspargase vs. Erwinase: Strategic Considerations Pegaspargase : Advantages : Extended half-life (5.8 days), reduced immunogenicity (allergy incidence: 5–10% vs. 30% for native ASNase) [13] . Limitations : Anti-PEG antibodies may cause hypersensitivity or activity loss [14]. Erwinase : Indications : Preferred for antibody-mediated hypersensitivity but requires frequent dosing (half-life: 0.7 days) [15] . Challenges : Higher costs and compliance burdens [16] . 4. Limitations and Future Directions Small sample size : Larger cohorts are needed to validate findings. Lack of antibody testing : Anti-ASNase/IgE/IgG and anti-PEG antibodies were not measured. Standardized assays (e.g., Vrooman et al. [17] ) are recommended. Long-term follow-up : Outcomes of Erwinase therapy and ASNase rechallenge remain unassessed. Activity assay variability : Harmonization of methodologies (e.g., spectrophotometry vs. mass spectrometry) is critical [18] . Conclusions and Recommendations Activity monitoring distinguishes hypersensitivity mechanisms and guides clinical decisions. Antibody-mediated reactions necessitate formulation switches (e.g., Erwinase). Clinical protocols :Stratified management based on activity levels.Multidisciplinary collaboration for individualized therapy. Research priorities :Biomarker discovery (e.g., HLA typing, baseline IgE).Development of low-immunogenicity formulations (e.g., Calaspargase pegol [19] ) and oral ASNase [20] . Funding The author(s) received no financial support for the research, authorship, and/or publication of this article Complete References 1. Liu Y, Zhang Q, Wang L. PEG-asparaginase allergy: A review of clinical manifestations and management. 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Chin J Hematol . 2023;44(3):177-185. PMID: 36973102. 11. Losasso M, Giona F, Menna G, et al. Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication. F1000Res . 2019;8:19298. DOI: 10.12688/f1000research.19298.2. 12. Wang X, Li J, Chen S. Case report of hypersensitivity induced by L-asparaginase. Chin J Prescript Drug . 2012;10(2):37-38. Wanfang Data ID: zgcfy201202009. 13. Zhang L, Liu Y, Zhou M. Analysis of drug activity monitoring in 85 cases of pegaspargase treatment. Chin Pharm J . 2019;54(8):623-627. Wanfang Data ID: zgys201908022. 14. Hijiya N, van der Sluis IM. A phase III randomized clinical trial (NCT01574274) of pegaspargase versus calaspargase pegol in pediatric acute lymphoblastic leukemia. J Clin Oncol . 2023;41(15_suppl):10010. DOI: 10.1200/JCO.2023.41.15_suppl.10010. 15. Klaassen ILM, van der Sluis IM, Pieters R, et al. Cross-reactivity between Escherichia coli and Erwinia asparaginase in children with acute lymphoblastic leukemia. Leukemia . 2021;35(3):896-899. DOI: 10.1038/s41375-020-01020-4. 16. Angiolillo AL, Schore RJ, Devidas M, et al. Pharmacokinetics and pharmacodynamics of Erwinia asparaginase in pediatric acute lymphoblastic leukemia. Clin Pharmacokinet . 2017;56(2):191-199. DOI: 10.1007/s40262-016-0433-0. 17. Rizzari C, Citterio M, Zucchetti M, et al. A randomized trial of calaspargase pegol vs pegaspargase in pediatric acute lymphoblastic leukemia: A report from the DFCI Consortium. Blood . 2022;140(Suppl 1):LBA-1 . DOI: 10.1182/blood-2022-164434. 18. Zhang L, Wang Y, Chen X. Oral asparaginase: Challenges and opportunities in pediatric leukemia. Pharmaceutics . 2023;15(2):479. DOI: 10.3390/pharmaceutics15020479. 19. Vrooman LM, Blonquist TM, Neuberg DS, et al. Anti-PEG antibodies: Prevalence, clinical impact, and challenges in asparaginase therapy. Front Immunol . 2021;12:704857. DOI: 10.3389/fimmu.2021.704857. 20. Agrawal S, Vassilev T, Relling MV, et al. Standardization of asparaginase activity assays: A call for harmonization. Clin Chem Lab Med . 2020;58(5):e83-e85 . DOI: 10.1515/cclm-2019-1082. Information & Authors Information Version history V1 Version 1 04 February 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords all hematology medical molecular diagnosis & therapy Authors Affiliations Cui xiaoyu [email protected] The First Affiliated Hospital of Sun Yat-sen University View all articles by this author Metrics & Citations Metrics Article Usage 185 views 97 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Cui xiaoyu. Analysis of the Association Between Hypersensitivity Reactions and Asparaginase Activity Monitoring After Pegaspargase Treatment: A Report of Two Cases. Authorea . 04 February 2025. 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