Challenging, but not impossible: Oncologists share their best practices for predicting E. coli asparaginase allergies
Key Takeaways
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“Predicting which patients will develop an allergy is very difficult. Our best clinical and genetic markers can improve our best estimates, but many patients with risk factors won’t have an allergy, while many patients who have allergies don’t have any obvious risk factors.” — Seth Karol, MD, pediatric oncologist at St. Jude Children's Research Hospital
“Allergy is more common in adults compared to children, but this could be the result of increased use of pre-medication before asparaginase." — Ibrahim T. Aldoss, MD, board-certified oncologist, hematologist, and internist, City of Hope, Orange County, CA
Predicting Escherichia coli–derived asparaginase (ASNase)-induced allergic reaction in acute lymphoblastic leukemia (ALL) patients, especially in adolescent and young adult (AYA) patients, remains tricky. There's no one-size-fits-all test or gold-standard predictor, and hypersensitivity reactions are wildly variable and frustratingly unpredictable.
So, what can clinicians do? MDLinx spoke with experts to break down the latest thinking on risk stratification, monitoring, and emerging research.
Therapeutic drug monitoring (TDM)
Despite years of research, no single biomarker reliably predicts ASNase hypersensitivity. Age, prior exposure, even antibody testing are helpful, but not consistently predictive. That’s why most experts recommend switching focus: Instead of trying to predict a reaction, monitor for one in real time.
Therapeutic drug monitoring (TDM), specifically regular serum ASNase activity assessment, helps clinicians quickly catch “silent inactivation”—when the drug is neutralized without any obvious symptoms.[]
Related: Don’t miss this just because it’s rare: Unmasking a hidden threat for optimal ALL treatment in young adults“Predicting which patients will develop an allergy is very difficult," says, Seth Karol, MD, a pediatric oncologist at St. Jude Children's Research Hospital. "Our best clinical and genetic markers can improve our best estimates, but many patients with risk factors won’t have an allergy, while many patients who have allergies don’t have any obvious risk factors."
"For any patient who develops symptoms during their asparaginase therapy, testing asparaginase activity can be very helpful in finding those who have immune-mediated reactions,” Dr. Karol continues.
TDM helps differentiate between a hypersensitivity reaction and an infusion-related reaction (IRR). ASNase activity level ≥0.1 IU/mL often indicates IRR, whereas ASNase activity level <0.1 IU/mL likely indicates a true allergic HSR.[]
Post-induction treatment phase
Timing matters, too. Data from over 5,800 pediatric ALL patients show that allergic reactions spike after induction. Reactions during induction? Just 2%. But post-induction, that number jumps to 8%.[]
Why? Most likely immune sensitization—the body remembers the first exposure, and a later dose triggers a bigger response.
High-risk patient stratification
Patients classified as high-risk for ALL treatment protocols are more likely to develop allergic reactions to PEGasparaginase—around 14.4%, according to the meta-analysis.[]
Ibrahim T. Aldoss, MD, board-certified medical oncologist, hematologist, and internist from City of Hope in Orange County, CA, says age may also play a role: “Allergy is more common in adults compared to children, but this could be the result of increased use of pre-medication before asparaginase. Another factor is asparaginase formulation.”
A study published in Blood Cancer Journal discusses the prognostic significance of cytogenetic abnormalities in ALL, highlighting how some genetic alterations, such as the Philadelphia chromosome, are associated with poorer outcomes.[] Specific immunophenotypes, such as T-cell ALL, can also influence risk stratification and treatment decisions.[]
Promising biomarker research
A recent murine study provides valuable insights into predictive biomarkers for hypersensitivity reactions to asparaginase.[] The following biomarkers have been strongly correlated with the severity of asparaginase-induced hypersensitivity reactions:
Anti-ASNase Antibodies (IgG and IgE): Elevated levels of IgG and IgE antibodies against asparaginase were correlated with more severe reactions. Particularly, high titers of anti-ASNase IgG antibodies facilitated the formation of immune complexes (ICs) that increased hypersensitivity severity.
Immune Complexes: Levels of ASNase-specific ICs served as significant independent predictors of hypersensitivity severity. These ICs actively bind to immune cells, intensifying the immune response.
Basophil Activation and Binding: Binding of ASNase to leukocytes (CD45+) and basophils (IgE+ CD49b+) strongly correlated with hypersensitivity reactions. Basophil activation, measured through changes in CD200R1 and CD200R3 expression, was directly linked to reaction severity. Importantly, basophil depletion experiments demonstrated that basophils not only indicate a risk of reaction but also directly mediate hypersensitivity.
Genes may hold some answers
There’s also evidence that certain genetic traits increase the odds of ASNase hypersensitivity. One standout: the HLA-DRB107:01 allele. Pediatric ALL patients who carry this variant have shown significantly higher reaction rates.
While genotyping isn’t standard yet, it’s a possible tool for future risk stratification.[]
Actionable recommendations for clinicians
Experts recommend the following:
Incorporate comprehensive allergy histories into initial patient evaluations to identify potential hypersensitivity risks.
Regularly monitor ASNase activity levels to detect silent inactivation and adjust treatment protocols accordingly.
Train staff to recognize early, non-specific signs of hypersensitivity and establish protocols for prompt management.
And, ideally, have a backup plan: Be ready to pivot to alternative ASNase formulations in the event of hypersensitivity, ensuring minimal disruption to treatment plans.