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Asparaginase in ALL
Optimizing Asparaginase Therapy Across the Age Spectrum in ALL

Released: July 31, 2025

Keith J. August
Keith J. August, MD, MS
Emily Curran
Emily Curran, MD
Van Huynh
Van Huynh, MD
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Key Takeaways
  • Hypersensitivity reactions to pegylated asparaginase formulations should prompt a switch to Erwinia-derived asparaginase, not discontinuation.
  • Silent inactivation of asparaginase is asymptomatic and associated with worse outcomes; therapeutic drug monitoring can help detect and address silent inactivation.
  • The risk of asparaginase-associated toxicities like thrombosis, pancreatitis, and hepatotoxicity increases with age but can often be effectively managed via dose adjustments and/or supportive care.

This commentary captures highlights and practical clinical insights from a live symposium titled “Optimizing Asparaginase Therapy: Navigating Evolving Clinical Challenges in Pediatric and AYA ALL for Improved Outcomes” with Keith J. August, MD, MS; Emily Curran, MD; and Van Huynh, MD, held May 7, 2025, in Louisville, Kentucky, at the American Society of Pediatric Hematology/Oncology annual meeting.

Emily Curran, MD:
Asparaginase therapy has been a cornerstone of pediatric acute lymphoblastic leukemia (ALL) treatment since the 1970s, dramatically contributing to overall survival rates of nearly 90% in children. Its mechanism of action (ie, depleting extracellular asparagine to selectively kill leukemic blasts) has made it a uniquely effective component of contemporary treatment regimens. However, although pediatric patients have experienced remarkable outcomes, adolescents and young adults (AYAs) and adult patients with ALL have not benefited from asparaginase to the same degree.

Despite robust evidence supporting pediatric-based protocols in AYAs, most adult patients in real-world settings are treated with regimens developed for an older patient population in large part because of concerns about managing asparaginase-related toxicities. The underuse of pediatric-based regimens in AYAs and adult patients represents a missed opportunity for improved survival and underscores the need for shared strategies across disciplines to ensure safe and effective asparaginase exposure.

Case Challenges 

Van Huynh, MD:
Let us consider the case of a 6-year-old patient diagnosed with T-cell ALL with high-risk features, including a white blood cell count of 384,000 cells/μL at diagnosis and CNS-2 disease. The child received an induction dose of pegylated asparaginase and was scheduled for 4-6 additional doses. However, after the initial infusion, the patient developed vomiting, stomachache, and rash, raising concerns for hypersensitivity. Of note, there were no hives or respiratory symptoms. This scenario prompts important clinical questions: Was this a true allergic reaction, and should therapy be altered? 

The timing and presentation suggest this is not a true hypersensitivity reaction. Instead, it is likely an infusion reaction, especially given that this is the patient's first exposure to asparaginase. My recommendation would be to check asparaginase activity levels to confirm adequate enzyme activity and continue with the same agent, using premedications for future doses.

Let’s look at another case. A 12-year-old patient with B-cell ALL developed a grade 3 hypersensitivity reaction after the second dose of pegylated asparaginase during consolidation. The reaction included rash, stomachache, bronchospasm, and hypotension, which are classic signs of an immediate-type hypersensitivity. This is a true hypersensitivity reaction, and continuing with the same asparaginase formulation would risk severe harm and ineffectiveness because of the presence of neutralizing antibodies. My recommendation would be an immediate switch to a noncross-reactive Erwinia-derived asparaginase product.

Understanding Hypersensitivity: Recognizing When to Switch Therapy

Van Huynh, MD:
Hypersensitivity reactions to asparaginase may occur in 10% to 30% of patients and are typically immune mediated. They can occur following the initial dose but often manifest during consolidation or later phases. A true hypersensitivity reaction is rare during first exposure. The hallmark features (ie, rash, wheezing, hypotension, and bronchospasm) distinguish these events from nonspecific symptoms like flushing or abdominal pain. Such reactions are typically mediated by antidrug antibodies that neutralize asparaginase activity and can pose life-threatening risks if the drug is readministered.

Of importance, Escherichia coli–derived asparaginase does not cross-react with Erwinia asparaginase, as evidenced in a report from the Children’s Oncology Group (COG) that demonstrated similar outcomes among patients who received Erwinia asparaginase following discontinuation of E coli–derived asparaginase because of toxicity and those who received all scheduled doses, allowing safe substitution and therapy completion.

Keith J. August, MD, MS:
At present, the use of premedication with H1/H2 blockers with or without steroids is common practice, though its efficacy remains a topic of debate. Although one retrospective chart review suggested that universal premedication reduces the rate of acute adverse events, other centers have not found consistent benefit. In addition, it is important to keep in mind that premedication blunts the reaction but does not mitigate asparaginase inactivation.

Silent Inactivation and the Role of Therapeutic Drug Monitoring 

Van Huynh, MD:
Another issue relevant to the clinical use of asparaginase is silent inactivation, a phenomenon in which neutralizing antibodies render asparaginase inactive without causing clinical hypersensitivity. Approximately 30% of patients experience silent inactivation, and without therapeutic drug monitoring, it can go undetected, undermining treatment.

Keith J. August, MD, MS:
Therapeutic drug monitoring is important for identifying silent inactivation. COG guidelines outline thresholds for serum asparaginase activity levels at indicated times postinfusion that guide care. For example, for pegylated asparaginase, activity levels should be checked at 7 and 14 days post infusion. Levels <0.1 IU/mL at 7 days indicate inadequate activity that necessitates a switch to the Erwinia formulation. For the Erwinia formulation, guideline recommendations are limited. Trough levels should be monitored with consideration of adjusting to every-other-day dosing if the serum asparaginase activity at 72 hours postinfusion is <0.1 IU/mL.

Common Adverse Events Associated With Asparaginase and Management Recommendations 

Van Huynh, MD:
Toxicity is a major concern that limits the use of pediatric-inspired regimens in AYAs with ALL. The risk of class-specific toxicities (ie, hepatotoxicity, thrombotic events, pancreatitis) increases with age, as shown in the NOPHO ALL2008 study of more than 1500 patients. AYAs were more likely to experience several toxicities compared with children younger than 10 years of age, underscoring the need for age-adapted strategies.

Hepatotoxicity presents as elevations in bilirubin and transaminases and is expected but rarely progresses to liver failure. These changes are typically reversible within 4-6 weeks and do not justify discontinuing asparaginase unless accompanied by significant clinical deterioration. Strategies to mitigate hepatotoxicity include holding hepatotoxic comedications and supplementation with L-carnitine for patients at high risk (eg, older age, obese). In adults experiencing hepatotoxicity, asparaginase doses can be capped, and prophylactic L-carnitine has demonstrated some potential protective effects.

Thrombotic complications are also more common in AYAs and adults. Most events are venous (eg, deep vein thrombosis or pulmonary embolism) and can be managed with appropriate anticoagulation therapy. For non-CNS events, reintroduction of asparaginase is often possible after stabilization.

Pancreatitis also warrants caution. Mild or laboratory-only elevations in amylase or lipase, which can be referred to as chemical pancreatitis, may not require asparaginase discontinuation, but clinical pancreatitis—defined as at least 2 of the following: abdominal pain, serum amylase or lipase elevation, and imaging findings—often leads to asparaginase being held or discontinued. The risk of relapse after rechallenge is high. Each case should be evaluated individually, keeping the patient’s risk profile in mind.

Looking Ahead: Targeted Therapies and Evolving Regimens 

Keith J. August, MD, MS:
Looking to the future, novel agents may help reduce the total burden of asparaginase without compromising outcomes. For example, both the phase II St Jude Children’s Research Hospital SJALL23H trial (NCT06533748) and the phase III COG AALL1732 trial (NCT03959085) are examining regimens that reduce asparaginase exposure while adding immunotherapies like blinatumomab and inotuzumab ozogamicin in pediatric and adult patients with ALL. These data may shift the paradigm in the coming years, allowing for fewer doses of asparaginase without sacrificing the depth of response or survival outcomes.

Your Thoughts
Have you adopted routine use of pediatric regimens for your AYA (and adult) patients with ALL? What have been your experiences caring for patients with ALL of all ages with various treatment regimens? 

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