Is it an allergy or something else? Differentiating reactions to E. coli asparaginase

By Alpana Mohta, MD, DNB, FEADV, FIADVL, IFAAD | Fact-checked by Barbara Bekiesz

Published April 22, 2025

Key Takeaways

Industry Buzz

“Symptoms such as fever, rash, hypotension, and respiratory distress are not exclusive to hypersensitivity, [so] distinguishing between these possibilities is vital to ensure appropriate treatment adjustments and avoid unnecessary discontinuation of asparaginase therapy." — Ibrahim T. Aldoss, MD, board-certified oncologist, hematologist, and internist, City of Hope, Orange County, CA

Hypersensitivity reactions to pegylated E. coli asparaginase (PEG-ASNase) can be a real challenge when treating acute lymphoblastic leukemia (ALL). This is because there are a number of other conditions that can show up with similar symptoms. So, diagnosing it accurately is key to making sure we treat it right.

According to Ibrahim T. Aldoss, MD, a board-certified medical oncologist, hematologist, and internist at City of Hope in Orange County, CA, “Asparaginase is a cornerstone in ALL therapy, but its administration can lead to hypersensitivity reactions in a subset of patients. These reactions can range from mild allergic responses to severe anaphylaxis."

"However, symptoms such as fever, rash, hypotension, and respiratory distress are not exclusive to hypersensitivity and may overlap with other serious conditions. Distinguishing between these possibilities is vital to ensure appropriate treatment adjustments and avoid unnecessary discontinuation of asparaginase therapy," Dr. Aldoss tells MDLinx.

Let’s dive into what to watch out for when PEG-ASNase hypersensitivity is on the table.

Differential diagnoses to consider

Tumor lysis syndrome (TLS)

TLS is an oncologic emergency resulting from the rapid lysis of tumor cells, leading to the release of their contents into the bloodstream. This can cause a number of metabolic issues, such as hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia.^[]

What to look for:

Nausea and vomiting
Lethargy
Seizures
Cardiac arrhythmias
Acute kidney injury

How to tell TLS apart:

TLS typically occurs within 12 to 72 hours after initiating chemotherapy.
Laboratory findings are key to diagnosis, including elevated uric acid, potassium, and phosphate levels, along with decreased calcium levels.^[]

For suspected TLS, oncologists recommend evaluation of electrolytes, renal function, and uric acid levels.

Cytokine release syndrome (CRS)

CRS is a systemic inflammatory response triggered by the release of cytokines from immune cells, often in reaction to certain immunotherapies.^[]

What to look for:

Fever
Hypotension
Tachycardia
Hypoxia
Multi-organ dysfunction in severe cases

How to tell CRS apart:

CRS is commonly associated with therapies like monoclonal antibodies and CAR-T cell treatments.
The onset is usually within hours to days post-infusion.
Elevated serum cytokine levels (eg, IL-6) can aid in diagnosis.

Silent inactivation of asparaginase

Silent inactivation happens when the body creates antibodies against asparaginase, but without showing any obvious symptoms of an allergic reaction. This can result in a drop in the drug’s effectiveness, even though the patient might seem fine.^[]^[]

What to look for:

Often asymptomatic
Possible subtle signs like fatigue or increased minimal residual disease

How to tell it apart:

Therapeutic drug monitoring (TDM) reveals subtherapeutic asparaginase activity levels.
Absence of clinical allergic symptoms despite antibody presence.

What can help diagnose these conditions?

There’s no formal, one-size-fits-all diagnostic tool for PEG-ASNase allergy. However, research has shown that there are a few signs to help make the call.

For example, research from St. Jude’s found that the presence of anti-PEG-ASP IgG antibodies is strongly tied to hypersensitivity reactions and a quicker breakdown of the drug. In fact, angioedema during the first reaction is considered a solid indicator of an immune-mediated allergy. Common symptoms like vomiting or low blood pressure are less specific, as they can overlap with other reactions.

Seth Karol, MD, pediatric oncologist at St. Jude Children’s Research Hospital, adds, “Our research suggests that angioedema at the time of suspected allergy is the best differentiator of an immune-mediated reaction from mimics such as infusion-related reactions or chemotherapy-induced nausea.”

Experts agree that when a patient on PEG-ASNase shows signs of hypersensitivity, it’s crucial to carefully assess the timing of symptoms in relation to the drug’s administration.

Adam Cloe, MD, FCAP, co-director of hematopathology at Los Angeles General Medical Center, emphasizes that regular monitoring of serum ASNase activity through TDM can identify silent inactivation, allowing for timely intervention.