In 2024 alone, over 6,100 new cases of acute lymphoblastic leukaemia (ALL) were diagnosed nationwide, with the disease striking hardest in the youngest. Nearly one in four childhood cancers is a form of leukaemia, and ALL is the leading subtype.

Cancer Stat Facts: Leukaemia — Acute Lymphocytic Leukaemia (ALL). National Cancer Institute, SEER.

Childhood and Adolescent Blood Cancer Facts and Statistics. Leukaemia & Lymphoma Society.

Asparaginase (ASNase) is foundational in multi-agent chemotherapy regimens for ALL, especially in adolescent and young adult (AYA) cohorts. 

Why allergies may be missed

Allergic risk is traditionally emphasised in pediatric protocols. Many oncologists presume a lower incidence in older cohorts, which has not held true in recent data.

According to a recent expert panel consensus paper, hypersensitivity reactions occur in roughly 10%–30% of patients with native E. coli ASNase and 3%–24% with PEG-ASNase. Patients previously exposed to ASNase formulations have increased risks of allergic reactions upon re-exposure.

Curran E, Luskin MR, Alachkar H, et al. Recognition, prevention, and management of adverse events associated with asparaginase/pegaspargase treatment of acute lymphoblastic leukaemia in adults: consensus of an expert panel. Haematologica. 2025 Mar 20. [Epub ahead of print]

In pediatric and AYA cohorts, hypersensitivity reactions  to PEG-ASNase have been reported in  3.3%

van der Sluis IM, Brigitha LJ, Fiocco M, et al. Continuous PEGasparaginase dosing reduces hypersensitivity reactions in pediatric ALL: A Dutch Childhood Oncology Group ALL11 randomised trial. J Clin Oncol. 2024;42(14):1676–1686.

and 7.7%

Rizzari C, Möricke A, Valsecchi MG, et al. Incidence and characteristics of hypersensitivity reactions to PEG-asparaginase observed in 6136 children with acute lymphoblastic leukaemia enrolled in the AIEOP-BFM ALL 2009 study protocol. Hemasphere. 2023;7(6):e893.

of patients, respectively. The reactions range from mild cutaneous eruptions to severe anaphylaxis. Despite these rates, delayed diagnosis and misattribution of symptoms remain common in the AYA setting, where allergic reactions may mimic common chemotherapy-associated complications or be disregarded as transient.

Ibrahim T. Aldoss, MD, board-certified medical oncologist, haematologist, and internist from City of Hope in Orange County, CA, further elaborates: “Symptoms such as fever, rash, hypotension, or GI discomfort may be confused with chemotherapy side effects, cytokine release, infection, or even tumour lysis syndrome. Furthermore, asparaginase allergy can be silent— a ‘silent hypersensitivity’—without clinical symptoms, but it can inactivate the drug and make it ineffective.” Such patients appear clinically stable but experience rapid ASNase clearance, leading to therapeutic failure.

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 Mar;101(3):279–285.

Delayed intervention may also lead to more severe reactions upon subsequent exposure.

Swanson HD, Panetta JC, Barkeret PJ, et al. Predicting the success of desensitisation after pegaspargase allergy. Blood. 2020 Jan 2;135(1):71–75.

Clinical consequences

Failure to recognise and appropriately manage E. coli ASNase allergy can compromise remission induction and increase relapse risk.

A study analysing young adults aged 17 to 39 years, with ALL treated on the CALGB 10403 protocol, found that early discontinuation of PEG-ASNase was common, occurring in approximately 32% of patients. This early discontinuation was associated with inferior survival outcomes, particularly in standard-risk patients.

Aldoss I, Yin J, Wall A, et al. The impact of early PEG-asparaginase discontinuation in young adults with ALL: a post hoc analysis of the CALGB 10403 study. Blood Adv. 2023 Jan 24;7(2):196–204.

How to recognise and diagnose

Researchers at St. Jude’s Children’s Research Hospital have studied the clinical characteristics of PEG-ASNase hypersensitivity reactions.

Browne EK, Moore C, Sykes A, et al. Clinical characteristics of intravenous PEG-asparaginase hypersensitivity reactions in patients undergoing treatment for acute lymphoblastic leukaemia [Formula: see text]. J Pediatr Oncol Nurs. 2018;35(2):103–109.

Mild to moderate reactions may present as transient flushing, rash, urticaria, or low-grade fever. More severe grade 3 reactions, which accounted for over 70% of documented cases, typically involve bronchospasm, hypotension, angioedema, or a constellation of allergy-related symptoms that necessitate immediate pharmacologic intervention. 

The onset of these reactions is typically acute, with the vast majority occurring within 60 minutes of infusion initiation. The median time to symptom onset is around 7.5 minutes. Despite the fact that most reactions occur during the infusion itself, delayed reactions, while rare,  have been documented. The longest lag time reported was 199 minutes after initiation.

Life-threatening anaphylaxis (grade 4) is rare but has been reported. Common symptoms include dyspnea, pruritus, vomiting, cough, and oedema, either localised or generalised.

After the diagnosis

From a clinical practice perspective, hypersensitivity reactions necessitate both immediate and long-term management strategies. Patients experiencing significant reactions should be promptly treated with supportive care and may require discontinuation of PEG-ASNase. In such cases, an alternative formulation, such as Erwinia asparaginase, should be substituted without delay to preserve the antileukemic effect of asparagine depletion.

Browne EK, Moore C, Sykes A, et al. Clinical characteristics of intravenous PEG-asparaginase hypersensitivity reactions in patients undergoing treatment for acute lymphoblastic leukaemia [Formula: see text]. J Pediatr Oncol Nurs. 2018;35(2):103–109.