Asparaginase Hypersensitivity: Immune Reactions of a Key Tool Against ALL

L-asparaginase is a critical component of multidrug treatment regimens for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). Asparaginase is an enzyme that breaks down the amino acid asparagine. Normal cells can synthesize asparagine, but ALL and LBL cells cannot, and therefore depend on asparagine made by nearby healthy cells. Asparaginase therapy reduces how much extracellular asparagine is available to malignant cells.¹ It is administered intravenously or intramuscularly. Inclusion of asparaginase in ALL treatment regimens has improved outcomes.^2,3  

Unfortunately, L-asparaginase is commonly associated with immune hypersensitivity reactions and other side effects that disrupt treatment and can threaten patients’ lives, including pancreatitis, thromboembolism, hyperammonemia, hyperbilirubinemia, and hyperglycemia. Discontinuing asparaginase is associated with poorer treatment efficacy and prognosis, but asparaginase toxicities are often reversible and manageable if detected early, so monitoring for and quickly detecting these side effects is crucially important.^2,3 

Oncology nurses should educate patients and families about the potential side effects of asparaginase, monitor patients for signs and symptoms of asparaginase toxicities (immediately reporting suspected toxicities to the patient’s oncologist), and play a central role in managing asparaginase toxicities. By understanding the management of asparaginase toxicity, oncology nurses can help to ensure that their patients receive timely, safe, and effective treatment.

“Asparaginase toxicities are unique,” noted Ibrahim Aldoss, MD, of the City of Hope Medical Center in Duarte, California, and Dan Douer, MD, of the University of Southern California in Los Angeles.² Even though asparaginase’s antitumor properties were first discovered more than 50 years ago, its molecular mechanisms and pathophysiology remain unclear, they wrote.²

Nor are patient risk factors for asparaginase hypersensitivity well understood, although younger patients and those who have not received premedication appear to be at higher risk of symptomatic hypersensitivity.^2-4 Hypersensitivity also appears to be more common in children receiving asparaginase without concurrent rituximab.^2,3 

There appear to be genetic risk factors, particularly human leukocyte antigen (HLA) HLA-DRB1*07:01 variants and certain gene mutations involved in immune response regulation and asparagine metabolism pathways.^5,6 

At the 2023 Congress of the International Society of Paediatric Oncology, medical geneticist Spencer J. Anderson, PhD, of the University of British Columbia in Canada, reported that mutations in CYP1B1 and immune regulation pathways such as ANKLE2 identified in a genome-wide association study were associated with a six-fold increased risk of L-asparaginase hypersensitivity among nearly 1000 children undergoing ALL treatment.⁶ Sixty-one percent of children with those risk variants experienced hypersensitivity reactions, Anderson reported. If those associations are confirmed in other studies, gene panel tests might be developed in the future that could identify children at increased risk, informing treatment decision making.

Because asparaginase medications are bacterial enzymes, they can provoke an immune overreaction. These immune hypersensitivity reactions can range from mild rash, hives or itching, to severe and potentially life-threatening allergic anaphylaxis that can cause swelling of the throat, difficulty breathing, and low blood pressure.^1-4 The development of asparaginase-neutralizing antibodies, either in association with hypersensitivity reactions or in cases of “silent inactivation” that have no clinical symptoms of allergy, can lead to treatment failure and disease progression.⁷ 

Three main formulations of L-asparaginase are used in clinical oncology, each of which is associated with different risks of immune hypersensitivity:

• Escherichia coli-derived asparaginase The oldest form of asparaginase, also frequently known as native E. coli-asparaginase, is also the most likely to cause hypersensitivity reactions, affecting between 30% and 75% of patients.⁸
• Pegylated asparaginase (PEG-asparaginase) This long-acting form of E. coli-derived asparaginase is less likely to cause hypersensitivity reactions than native E. coli asparaginase, but it is also more expensive — and in adults with ALL, it is associated with a higher risk of venous thromboembolism (VTE) than native E. coli.⁹ It was approved in 2006 as part of a chemotherapy for ALL.¹⁰ 
• Erwinia chrysanthemi-derived asparaginase: This medication is less likely to cause hypersensitivity reactions than E. coli-derived asparaginase and is used when patients have allergic reactions to asparaginase derived from E. coli. In 2021, in part to address global shortages in Erwinia asparaginase, the Food and Drug Administration approved a recombinant formulation, asparaginase Erwinia chrysanthemi (recombinant)-rywn), as one component of a chemotherapy regimen for the treatment of ALL and LBL in adults and children aged 1 month and older who have developed hypersensitivity to E. coli-derived asparaginase.¹