Benefits and challenges of switching pediatric ALL patients to asparaginase alternatives
Key Takeaways
Industry Buzz
“The main advantage of switching patients earlier is maintaining asparagine depletion, the core mechanism behind asparaginase’s efficacy. Failure to achieve or maintain adequate asparaginase exposure has been associated with increased risk of relapse, making timely substitution crucial.” — Ibrahim T. Aldoss, MD, board-certified medical oncologist, hematologist, and internist from City of Hope in Orange County, CA
Hypersensitivity reactions, silent inactivation, and toxicity can necessitate early discontinuation of pegylated Escherichia coli asparaginase (PEG-ASNase) in acute lymphoblastic leukemia (ALL) patients.
However, these interruptions can have catastrophic consequences in pediatric cases.
Here, we’ve outlined the top benefits and challenges of switching pediatric ALL patients to non-cross-reactive asparaginase alternatives.
Benefits of asparaginase alternatives
Erwinia ASNase and recombinant JZP-458 (Rylaze) are non-cross-reactive agents, meaning they do not provoke allergic responses in patients who have previously reacted to PEG-ASNase. This significantly reduces the risk of recurrent hypersensitivity.
Related: Forced to rethink ALL treatment: 6 reasons asparaginase treatment in children often fails—and viable alternativesThe Children's Oncology Group AALL1931 study[] utilized JZP-458 at doses of 25 mg/m² on Monday and Wednesday, and 50 mg/m² on Friday in one of the intramuscular (IM) cohorts. In these patients, 90% maintained nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at 72 hours post-dose.
Preserving asparaginase exposure also helps sustain dose intensity and improve event-free survival (EFS). Studies have shown that truncation of asparaginase therapy, whether due to toxicity or silent inactivation, has a significantly higher risk of relapse compared to outcomes in patients who complete the therapy.[]
"The main advantage of switching patients earlier is maintaining asparagine depletion, the core mechanism behind asparaginase’s efficacy. Failure to achieve or maintain adequate asparaginase exposure has been associated with increased risk of relapse, making timely substitution crucial."
— Ibrahim T. Aldoss, MD
Top challenges
Despite these benefits, switching to an alternative ASNase formulation poses several practical and clinical challenges, particularly in the pediatric population.
1. Complexity dosing and schedules
Seth Karol, MD, a pediatric oncologist at St. Jude Children's Research Hospital, says, “Alternative asparaginase formulations need to be given multiple times a week. This can be a significant time burden on patients. Because of how effective asparaginase therapy is, this burden is usually worth it, but future work will hopefully reduce this burden. Until then, patients and providers need to work together to find ways to overcome the challenges of existing therapy.”
Erwinia ASNase and JZP-458 have shorter half-lives than PEG-ASNase, thus requiring intramuscular or intravenous administration two to three times per week. Repeated hospital visits can disrupt school attendance, cause needle-related anxiety, and increase caregiver burden, particularly for younger children who rely entirely on parental support and may experience higher distress from invasive procedures.
Related: When a child's ALL treatment deviates, caregiver support is critical: Here's how to help manage mental health challenges2. Access and availability
Historically, there have been global supply shortages of Erwinia ASNase, leading to treatment delays or discontinuation. While JZP-458 was introduced to mitigate these supply chain issues, not all treatment centers stock it, and reimbursement may be inconsistent.[]
3. Toxicity monitoring
Like PEG-ASNase, both Erwinia ASNase and JZP-458 are associated with hepatotoxicity, pancreatitis, and thrombotic events.[]
4. Adherence
Adherence becomes a logistical and emotional challenge, not because parents forget appointments, but because each dose may involve distressing experiences for the child. Inadequate dosing or delays caused by missed visits or injection refusal may lead to suboptimal asparagine depletion, impacting event-free survival. Studies have shown that interruptions in asparaginase therapy correlate with inferior outcomes, reinforcing the need for child-friendly administration schedules and improved support systems.[]
Best practices for switching asparaginase in children
A strategic and patient-centered approach is essential to overcome these challenges and maximize the benefits of switching.
Measuring serum asparaginase activity is vital to confirm that the substituted agent maintains therapeutic levels. Nadir ASNase activity should be assessed 48–72 hours post-dose, depending on the dosing schedule, with a target threshold of ≥0.1 IU/mL. TDM is also essential to detect silent inactivation.[]
Ibrahim T. Aldoss, MD, board-certified medical oncologist, hematologist, and internist from City of Hope in Orange County, CA, recommends that the process of switching should involve pharmacists, nurses, infusion center coordinators, and social workers. Psychosocial screening and flexible schedules, such as extended infusion center hours or home infusion options, can support adherence for children.
He adds, “Patients should be informed about why the switch is necessary, what to expect regarding dosing frequency, and the importance of sticking to the schedule. Digital tools like mobile reminders or telehealth check-ins can aid adherence.”
Read Next: 4 missed opportunities for boosting survival rates in pediatric ALL patients