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Monitoring for Asparaginase Reactions and Silent Inactivation
Monitoring for hypersensitivity, silent inactivation, and other asparaginase adverse events can be life-saving. Hypersensitivity typically emerges after the second dose.1
Patients should be routinely assessed for signs or symptoms of a hypersensitivity reaction. These include rash or urticaria (rashes with itchy, round, red welts), hives or angioedema, swelling, flushing, dyspnea, bronchospasm, hypotension, and anaphylaxis.1,2,8 Anaphylaxis is an acute inflammatory reaction associated with hypotension, difficulty breathing, dizziness, cyanosis, and loss of consciousness.
Declines in serum asparaginase activity (SAA) are a sign of asparaginase inactivation, so SAA is regularly measured in all patients for timely detection, weekly or more frequently if a patient is suspected to be at high risk for silent inactivation.1 (Asparaginase schedules vary depending on regimen and the formulation of asparaginase administered.) SAA levels of 0.1 IU/mL or higher are considered adequate for treatment efficacy.7 Lower levels can indicate inactivation.
Managing Asparaginase-Associated Adverse Events
Premedication with antihistamines and steroids can mitigate the severity of hypersensitivity but they mask clinical symptoms without addressing the underlying antibody-mediated processes that cause them, and therefore do not prevent asparaginase neutralization and silent asparaginase inactivation.1 SAA therapeutic drug monitoring is therefore important even when patients are premedicated.1
Asparaginase hypersensitivity reactions range from a mild rash to anaphylaxis. Management for asparaginase hypersensitivity reactions depend on the severity of the reaction, and algorithms differ depending on asparaginase formulation.1,2,11
Generally, asparaginase is withheld and reactions managed. Mild reactions may be managed with supportive care with antihistamines and hydrocortisone corticosteroid; severe reactions may require hospitalization and emergency treatment. Epinephrine and steroid are administered for cases of anaphylaxis.2
If the hypersensitivity reaction is mild, asparaginase dose may be reduced upon re-administration. In severe cases, or if the patient experiences silent inactivation, asparaginase may have to be discontinued entirely. Hypersensitivity reactions are sometimes mistaken for infusion reactions, but infusion reactions usually occur at the time of the first asparaginase dose and hypersensitivity typically emerges on or after the second dose.1
After a patient’s hypersensitivity reaction has resolved, multistep, formulation- and patient population-specific desensitization protocols may be attempted unless there is SAA therapeutic drug monitoring evidence of silent inactivation; in which case, it should not be used.12 Desensitization involves a temporary induction of toleration for the asparaginase formulation via slow, incremental administration, starting from a very small dose fraction and working back up to a full therapeutic dose.2 However, caution is warranted.
“Desensitization is a last resort approach, as it is not always effective and may be associated with adverse reactions,” warned professor Patrick W. Burke, MD, of the University of Michigan, and coauthors.11
The patient may also be switched to a different formulation of asparaginase (for example, from native E. coli to PEG-asparaginase, or from PEG-asparaginase to Erwinia asparaginase).2,3 However, cross-reactivity does sometimes occur between formulations and close, continued SAA monitoring, and monitoring of patients for clinical signs and symptoms of recurring hypersensitivity, is required.1
“If hypersensitivity occurs [with PEG-asparaginase], all subsequent doses of PEG asparaginase (including the dose that caused the reaction) should be switched to Erwinia asparaginase,” cautioned Dr Burke and coauthors.11 “Discontinuation of PEG asparaginase for hypersensitivity without replacing all subsequent scheduled PEG asparaginase doses with Erwinia asparaginase was associated with inferior disease-free survival.” Switching from PEG-asparaginase to Erwinia asparaginase afforded patients outcomes similar to uninterrupted delivery of planned doses of PEG-asparaginase, had hypersensitivity not occurred.11
References
1. Burke MJ, Zalewska-Szewczyk B. Hypersensitivity reactions to asparaginase therapy in acute lymphoblastic leukemia: immunology and clinical consequences. Future Oncol. 2022;18(10):1285-1299. doi:10.1217/fon-2021-1288
2. Aldoss I, Douer D. Asparaginase: understanding and overcoming toxicities. Clin Lymph Myeloma Leuk. 2021;21(Suppl 1):S90-S94. doi:10.1016/S2152-2650(21)01224-6
3. Aldous I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020;135(13):987-995. doi:10.1182/blood.2019002477
4. Battistel AP, da Rocha BS, dos Santos MT, Daudt LE, Michalowski MB. Allergic reactions to asparaginase: retrospective cohort study in pediatric patients with acute lymphoid leukemia. Hematol Transf Cell Ther. 2021;43(1):9-14. doi:10.1016/j.htct.2019.10.007
5. Fernandez CA, Smith C, Yang W, et al. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014;124(8):1266–1276. doi:10.1182/blood-2014-03-563742
6. Anderson SJ. L-asparaginase hypersensitivity reactions are associated with CYP1B1 and immune regulatory pathways. Presented at: 55th Congress of the International Society of Paediatric Oncology. October 11-14, 2023. Ottawa, Canada. Abstract O180.
7. van der Sluis IM, Vrooman LM, Pieters R, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279-285. doi:10.3324/haematol.2015.137380
8. Brigitha LJ, Fiocco M, Pieters R, et al; Ponte de Legno Toxicity Working Group. Hypersensitivity to pegylated E.coli asparaginase as first- line treatment in contemporary paediatric acute lymphoblastic leukaemia protocols: a meta-analysis of the Ponte di Legno Toxicity working group. Eur J Cancer. 2022;162:65-75. doi:10.1016/j.ejca.2021.11.016
9. Seki JT, Alsibai R, Atenafu EG, Chen R, Sibai H. Is native E coli- or Peg-ASP more thrombogenic in adult ALL? A systematic review and meta-analysis. Thromb Update. 2023;12:100143. doi:10.1016/j.tru.2023.100143
10. Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: pegaspargase (Oncaspar®) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist. 2007;12(8):991-998. doi:10.1634/theoncologist.12-8-991
11. Burke PW, Hoelzer D, Park JH, Schmiegelow K, Douer D. Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open-Cancer Horizons roundtable discussion. ESMO Open. 2020;5(5):e000858. doi:10.1136/esmoopen-2020-000858
12. Tong WH, Pieters R, Tissing WJE, van der Sluis IM. Desensitization protocol should not be used in acute lymphoblastic leukemia patients with silent inactivation of PEGasparaginase [Letters to the Editor]. Haematologica. 2014;99(7):e102–e104. doi:10.3324/haematol.2013.099663
