Introduction
Asparaginase is integral in the treatment of pediatric leukemia/lymphoma. Asparaginase levels can be measured in serum as a surrogate marker for asparagine depletion and resultant leukemic cell death. Monitoring of serum asparaginase levels has been validated as a method of quantifying the efficacy of asparaginase formulations.
Trough asparaginase levels of <0.1 IU/mL are likely subtherapeutic and may reflect the presence of anti-asparaginase antibodies in the patient’s blood. Pegaspargase (pegylated asparaginase) and Erwinia asparaginase formulations are available in Canada. Since pegaspargase is derived from E.coli, it is highly immunogenic and can cause clinically apparent hypersensitivity reactions (CARs) (i.e patient is reacting to the asparaginase portion of the drug) during or following administration [1]. Pegaspargase is asparaginase linked to polyethylene glycol which is compound that can itself cause an immune response. Immune-mediated reactions, both clinically apparent and subclinical, can contribute to the development of anti-asparaginase antibodies resulting in loss of therapeutic effect and reduced asparaginase serum levels. When this inactivation is subclinical it is termed silent inactivation (SI). SI has been reported in up to 8% of children who receive pegaspargase [2].
The presence of subtherapeutic levels or SI justifies a switch of asparaginase formulations from pegaspargase to Erwiniaasparaginase. Antibody cross-reactivity does not occur in patients treated with Erwinia who have neutralizing antibodies to pegaspargase, which allows for patients to achieve therapeutic levels of asparaginase with Erwinia . Erwinia is also less immunogenic than pegaspargase and thought to contribute less to anti-asparaginase antibody formation without compromising overall survival [2]. However, pegaspargase is preferred first-line asErwinia is less potent, more expensive and requires multiple injections, which impacts the practical administration of Erwiniaand the quality of life of patients.
Up to 30% of patients will develop clinical symptoms during pegaspargase infusion, such as flushing, tachycardia or hives [3]. These symptoms can be representative of an immune-mediated CAR (associated with a risk of low levels) or a non-immune mediated hypersensitivity/infusion-related reaction (not associated with low levels). These phenomena can be nearly impossible to distinguish clinically. The only way to reliably differentiate between an immune-mediated CAR and an infusion related reaction is by measuring asparaginase levels. Otherwise, patients with infusion related reactions to pegaspargase may be switched to Erwinia despite adequate asparaginase levels with pegasparagase.
There is concern that the use of clinical symptoms alone likely overestimates the true incidence of reactions to asparaginase and that of low serum levels. This is especially important to consider in light of the global shortage of Erwinia [3].
Despite this, routine asparaginase monitoring is not considered standard of care at all Canadian centers for reasons that are not entirely clear in the literature. Previously, there has been a lack of a widely available validated assay. However, Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories offer asparaginase testing on serum/plasma specimens. Regardless, academic centers in Canada appear to be varied in their approach to measuring levels and there are different clinical practices regarding when to switch asparaginase preparations, when to order asparaginase levels and how to use those levels to guide management.
The objective of this study is to identify variations in individual practice and experience regarding asparaginase activity monitoring and the management of clinical asparaginase reactions across Canada using a survey. This study will describe: (1) management of reactions, (2) use of asparaginase activity monitoring , (3) reasoning for modifying, discontinuing or switching asparaginase preparations from pegaspargase to Erwinia asparaginase.