Your young adult ALL patient has an E. coli asparaginase allergy; now what?

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

Published April 21, 2025

Key Takeaways

Industry Buzz

"Premedications do not appear to be effective at ensuring adequate asparaginase therapy in a patient who has an immune-mediated reaction to asparaginase. While it may be possible to mask the symptoms, the immune reaction causes the asparaginase to leave the body too quickly." — Seth Karol, MD, pediatric oncologist at St. Jude Children's Research Hospital

Dealing with hypersensitivity to E. coli-derived asparaginase (PEG-ASNase) is a tough challenge for oncologists, especially when it comes to treating adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

The reactions can be severe, and doctors need to make quick decisions to balance the treatment's effectiveness while minimizing risk. Here’s a rundown of options after confirming PEG-ASNase hypersensitivity.

What to do if hypersensitivity is suspected

When hypersensitivity is suspected—triggered by symptoms like hives, low blood pressure, or even anaphylaxis—the first step is to stop the PEG-ASNase immediately. Timely action is crucial to avoid further complications. But that’s not all. Oncologists also need to monitor the patient’s asparaginase levels.

Low asparaginase activity (less than 0.1 IU/mL), even without symptoms, might indicate silent inactivation of the drug. And that’s just as dangerous as a full-blown allergy, according to Adam Cloe, MD, FCAP, co-director of hematopathology at Los Angeles General Medical Center. In such cases, the drug should be replaced, but the next steps depend on the patient’s condition.

Consider the following options, per the experts.

Erwinia chrysanthemi–derived asparaginase (Erwinia ASNase)

For patients with confirmed allergy or inactivation, the standard of care is switching to Erwinia-derived asparaginase, which does not share immunologic cross-reactivity with E. coli formulations.^[] Native Erwinia ASNase (eg, Erwinase) is derived from a different bacterial species and has no cross-reactivity with PEG-ASNase. Its shorter half-life of 7.5 hr (IV) and 15.6 hr (IM) requires more frequent dosing (typically 25,000 IU/m² IM or IV three times per week).^[]

While effective for many, availability can be an issue, making it harder to access when needed most.

Recombinant Erwinia asparaginase (JZP-458/Rylaze)

Recombinant Erwinia ASNase (JZP-458; Rylaze) is a noncross-reactive PEG-ASNase alternative, FDA-approved in 2021.^[] It’s a game-changer for patients who need an alternative to PEG-ASNase. This version is biosynthetically identical to the native Erwinia enzyme and helps address supply shortages.

It is given in the dose of 25 mg/m² IM or IV every 48 hours (2–3x/week) to maintain nadir serum activity ≥0.1 IU/mL.^[]

Phase 2 trials showed 94% of patients maintained therapeutic enzyme activity, with no reported anaphylaxis in PEG-ASNase–allergic patients.^[]

Premedication: A controversial option

Some studies support routine premedication use to minimize hypersensitivity reactions, maintain treatment continuity, and reduce overall treatment costs.

One cost-effectiveness analysis found that premedication with antihistamines, antipyretics, and steroids, especially when combined with serum asparaginase level monitoring, was the most cost-effective strategy for children with ALL receiving PEG-ASNase.^[]

In standard-risk patients, this approach reduced treatment switches to Erwinia by 8%, and it added 0.01 QALYs and saved $4,586 compared to monitoring alone. It also outperformed the no-premedication/no-monitoring group by reducing switches by 3%, adding 0.08 QALYs, and saving $1,993.

In high-risk patients, premedication saved $29,757 over monitoring alone and $11,255 over no-premedication, with 7% and 2% fewer drug switches, respectively.

However, according to Seth Karol, MD, a pediatric oncologist at St. Jude Children's Research Hospital, “Premedications do not appear to be effective at ensuring adequate asparaginase therapy in a patient who has an immune-mediated reaction to asparaginase. While it may be possible to mask the symptoms, the immune reaction causes the asparaginase to leave the body too quickly (it dramatically increases the rate of drug clearance), and this prevents the asparaginase from being present long enough to be effective.”

Desensitization

In some cases, desensitization is an option for patients who need asparaginase but develop hypersensitivity reactions. It's more commonly done with native L-asparaginase than with pegaspargase, due to the latter’s longer half-life and higher risk of severe anaphylaxis upon re-exposure.

A study published in Pediatric Blood & Cancer investigated calaspargase pegol (CAL-PEG) desensitization in patients with hypersensitivity to pegaspargase.^[] The findings suggested that patients with persistent anti-pegaspargase antibodies who undergo desensitization are at risk for rapid drug clearance and may not maintain adequate asparaginase activity post-desensitization. The study emphasized the importance of monitoring antibody levels and asparaginase activity, noting that patients with prior angioedema and gastrointestinal symptoms are at higher risk for desensitization failure.

Desensitization’s role may be limited. A 2023 study published in Blood Advances indicated that desensitization to CAL-PEG appears to be less successful than with other asparaginase formulations.^[]

Dr. Karol points out that desensitization can work in some cases, especially if there’s a gap between the initial reaction and the desensitization attempt. “However, asparaginase activity levels should be checked to ensure the drug remains active long enough to be effective,” he says. “For patients where desensitization is not an option or has failed, switching to an alternative form of asparaginase, typically an Erwinia formulation, is appropriate.”

A last resort...

In rare cases, the decision may be made to stop asparaginase therapy altogether. Dr. Cloe emphasizes that this is a last resort, only for patients who experience severe, life-threatening reactions like anaphylaxis, or those who develop severe side effects like pancreatitis or blood clotting. In these instances, there may be no feasible alternatives, and discontinuing the drug becomes the only option.