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.