L-asparaginase activity and anti-L-asparaginase antibody as biomarkers in estimating PEG-asp-related anaphylaxis risk in childhood acute lymphoblastic leukemia patients

Main Article Content

Jiali Cui
Lian Jiang
Bei Xu
Yajie Bai


anaphylaxis risk, childhood acute lymphoblastic leukemia, L-asp activity, anti-L-asp antibody, PEG-asp


Background: L-Asparaginase (L-asp), the unconjugated form of polyethylene glycol-conjugated L-asparaginase (PEG-asp), regulates T cell stimulation, antibody production, and lysosomal protease activity to mediate PEG-asp-related anaphylaxis. This study aimed to investigate the relation of L-asp activity and anti-L-asp antibody with anaphylaxis risk and non-anaphylaxis adverse reaction risk in childhood acute lymphoblastic leukemia (ALL) patients who underwent PEG-asp contained therapy.

Methods: In total, 170 childhood ALL patients underwent PEG-asp-contained treatment and their L-asp activity and anti-L-asp antibody were detected on the 7th day after treatment initiation.

Results: There were 27 (15.9%) patients who had PEG-asp-related adverse reaction: 17 (10.0%) patients experienced PEG-asp-related anaphylaxis and 14 (8.2%) patients experienced PEG- asp-related non-anaphylaxis adverse reaction. Moreover, L-asp activity was negatively related to anti-L-asp antibody in childhood ALL patients (P<0.001). Elevated L-asp activity was associated with the absence of PEG-asp-related anaphylaxis (P<0.001), PEG-asp-related non-anaphylaxis adverse reaction (P=0.004), and PEG-asp-related adverse reaction (P<0.001). However, the anti- L-asp antibody displayed opposite trend similar to L-asp activity. Receiver operating characteristic (ROC) curve analyses exhibited L-asp activity and anti-L-asp antibody exhibited superior predictive values in estimating PEG-asp-related anaphylaxis risk with area under curve (AUC) of 0.955 and 0.905, respectively compared to PEG-asp-related non-anaphylaxis adverse reaction risk with AUC of 0.730 and 0.675, respectively. Besides, patients with de novo disease, higher risk stratification, and allergic history showed trends linked with PEG-asp-related anaphylaxis risk.

Conclusion: The monitoring of L-asp activity and anti-L-asp antibody maybe useful for early estimation and prevention of PEG-asp-related anaphylaxis in childhood ALL management.

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1. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020 Nov 1;105(11):2524–39. 10.3324/haematol.2020.247031

2. Jastaniah W, Essa MF, Ballourah W, Abosoudah I, Al Daama S, Algiraigri AH, et al. Incidence trends of childhood acute lymphoblastic leukemia in Saudi Arabia: Increasing incidence or competing risks? Cancer Epidemiol. 2020 Aug;67:101764. 10.1016/j.canep.2020.101764

3. Sasaki K, Jabbour E, Short NJ, Jain N, Ravandi F, Pui CH, et al. Acute lymphoblastic leukemia: A population-based study of outcome in the United States based on the surveillance, epidemiology, and end results (SEER) database, 1980–2017. Am J Hematol. 2021 Jun 1;96(6):650–8. 10.1002/ajh.26156

4. Ghasemian A, Al-Marzoqi AH, Al-Abodi HR, Alghanimi YK, Kadhum SA, Shokouhi Mostafavi SK, et al. Bacterial l-asparaginases for cancer therapy: Current knowledge and future perspectives. J Cell Physiol. 2019 Nov;234(11):19271–9. 10.1002/jcp.28563

5. Castro D, Marques ASC, Almeida MR, de Paiva GB, Bento HBS, Pedrolli DB, et al. L-asparaginase production review: bioprocess design and biochemical characteristics. Appl Microbiol Biotechnol. 2021 Jun;105(11):4515–34. 10.1007/s00253-021-11359-y

6. Fonseca MHG, Fiuza TDS, Morais SB, Souza T, Trevizani R. Circumventing the side effects of L-asparaginase. Biomed Pharmacother. 2021 Jul;139:111616. 10.1016/j.biopha.2021.111616

7. Riley DO, Schlefman JM, Vitzthum Von Eckstaedt VH, Morris AL, Keng MK, El Chaer F. Pegaspargase in Practice: Minimizing Toxicity, Maximizing Benefit. Curr Hematol Malig Rep. 2021 Jun;16(3):314–24. 10.1007/s11899-021-00638-0

8. Silva WFD, Massaut IHB, Bendlin RM, Rosa LI, Velloso E, Rego EM, et al. Toxicity Profile of PEG-Asparaginase in Adult Patients With Acute Lymphoblastic Leukemia in Brazil: A Multicenter Cross-Sectional Study. Clin Lymphoma Myeloma Leuk. 2020 Aug;20(8):e523-e8. 10.1016/j.clml.2020.04.001

9. Ovalle BP, Azocar MM, Nicklas DC, Villarroel CM, Morales VJ. [Hypersensitivity reactions associated with the use of asparaginase in children with acute lymphoblastic leukemia]. Andes Pediatr. 2021 Apr;92(2):182–92. 10.32641/andespediatr.v92i2.2151

10. Pichler WJ. Immune pathomechanism and classification of drug hypersensitivity. Allergy. 2019 Aug;74(8):1457–71. 10.1111/all.13765

11. Wu J, Chen C, Huang S, Shen S, Chen J, Zhang S. Correlation of L-asp Activity, Anti-L-asp Antibody, Asn and Gln With Adverse Events Especially Anaphylaxis Risks in PEG-asp-Contained Regime Treated Pediatric ALL Patients. Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820980113. 10.1177/1533033820980113

12. Subspecialty Group of Hematology tSoPCMA, Editorial Board CJoP, Subspecialty Group of Hematology the Society of Pediatrics Chinese Medical A, Editorial Board Chinese Journal of P. [Guidelines for the diagnosis and treatment of childhood acute lymphoblastic leukemia]. Zhonghua Er Ke Za Zhi. 2014 Sep;52(9):641–4.

13. Tang J, Yu J, Cai J, Zhang L, Hu S, Gao J, et al. Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation. Blood. 2021 Jul 29;138(4):331–43. 10.1182/blood.2020010438

14. World Health Organization (WHO), Uppsala Monitoring Centre. The use of the WHO-UMC system for standardised case causality assessment. Available at https://who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf

15. Koprivnikar J, McCloskey J, Faderl S. Safety, efficacy, and clinical utility of asparaginase in the treatment of adult patients with acute lymphoblastic leukemia. Onco Targets Ther. 2017;10:1413–22. 10.2147/OTT.S106810

16. Wang B, Relling MV, Storm MC, Woo MH, Ribeiro R, Pui CH, et al. Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients. Leukemia. 2003 Aug;17(8):1583–8. 10.1038/sj.leu.2403011

17. Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood. 2002 Mar 15;99(6):1986–94. 10.1182/blood.V99.6.1986

18. Liu C, Kawedia JD, Cheng C, Pei D, Fernandez CA, Cai X, et al. Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia. 2012 Nov;26(11): 2303–9. 10.1038/leu.2012.102

19. Kloos RQH, Pieters R, Jumelet FMV, de Groot-Kruseman HA, van den Bos C, van der Sluis IM. Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Mar 1;38(7):715–24. 10.1200/JCO.19.02292

20. Fernandez CA, Smith C, Yang W, Date M, Bashford D, Larsen E, et al. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014 Aug 21;124(8):1266–76. 10.1182/blood-2014-03-563742

21. Rathod S, Ramsey M, Relling MV, Finkelman FD, Fernandez CA. Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors FcepsilonRI and FcgammaRIII. Haematologica. 2019 Feb;104(2):319–29. 10.3324/haematol.2018.199448

22. Rodrigues MAD, Pimenta MV, Costa IM, Zenatti PP, Migita NA, Yunes JA, et al. Influence of lysosomal protease sensitivity in the immunogenicity of the antitumor biopharmaceutical asparaginase. Biochem Pharmacol. 2020 Dec;182:114230. 10.1016/j.bcp.2020.114230

23. Wallace AD, Francis SS, Ma X, McKean-Cowdin R, Selvin S, Whitehead TP, et al. Allergies and Childhood Acute Lymphoblastic Leukemia: A Case-Control Study and Meta-analysis. Cancer Epidemiol Biomarkers Prev. 2018 Oct;27(10):1142–50. 10.1158/1055-9965.EPI-17-0584

24. Lee WS, An J, Jung YH, Jee HM, Chae KY, Park YA, et al. Characteristics and Treatment of Anaphylaxis in Children Visiting a Pediatric Emergency Department in Korea. Biomed Res Int. 2020;2020:2014104. 10.1155/2020/2014104