Discussion
This is the first survey to measure the practice of asparaginase
activity monitoring and the management of reactions to pegaspargase
across pediatric oncologists and trainees in Canada. Respondents
represented 15 of 16 COG-affiliated centres with a variety of clinical
experience.
Clinicians primarily use IV pegaspargase which is consistent with COG
protocols. The only Canadian centres that routinely measure asparaginase
levels are the Hospital for Sick Children, McMaster University, CHU
Sainte-Justine, CHU de Quebec-Universite Laval and the IWK Health
Centre. Most respondents from these centres indicated they draw levels
at Day 0 and/or Day 6-7, which is consistent with expert recommendations
[5,6].
There is a range of target asparaginase levels across respondents, but
all target a level of at least 0.1 IU/mL, which is concordant with
standards of practice (SOP) at the Hospital for Sick Children and the
IWK Health Centre [5,6] and with consensus guidelines, all of which
suggest that a trough level <0.1 IU/mL is subtherapeutic
[5,6]. Most respondents noted that <10% of patients in
their practice have experienced low levels, which is consistent with the
cited prevalence of this phenomenon (8%) [2].
The most common reasons to modify therapy from pegaspargase toErwinia asparaginase was for a Grade 3-4 infusion reaction or for
asparaginase levels that are subtherapeutic, which is consistent with
most consensus guidelines [6]. COG protocols state that
discontinuation of pegaspargase is recommended for Grade 2 or
higher reactions, but only a Grade 3 or higher reaction mustswitch asparaginase preparations [3]. The National Comprehensive
Cancer Network (NCCN) clinical practice guidelines also support
switching asparaginase preparations in event of a Grade 3 reaction or
higher [5,7-9]. More recent COG protocols include a severity scale
suggestive that severe reactions warrant a switch to Erwiniaasparaginase but leave the definition of severe to the treating
institution [10,11].
The rate of hypersensitivity reactions to pegaspargase is reported to be
as high as 30% [7]. Despite this high prevalence, over 70% of
respondents stated they do not routinely administer pre-medications
before all doses of pegaspargase. Evidence suggests that premedication
can significantly reduce the rate of hypersensitivity reactions and
although premedication for all patients receiving pegaspargase is done
routinely in adult ALL protocols, this is not mandated in pediatric
protocols [12]. There is historical concern that premedication can
mask the development of a clinically relevant reaction that prior to the
availability of routine asparaginase assays was used as a sign of
anti-asparaginase antibody development and a required switch toErwinia asparaginase. All patients at the IWK receive
premedication prior to all asparaginase doses whether or not they have
previously experienced a reaction. These pre-medications include
acetaminophen, ondansetron, cetirizine, diphenhydramine, famotidine +/-
steroid.
One of the limitations of this study was the inability to contact every
practicing pediatric oncologist and subspecialty trainee in Canada.
However, the PIs personally reached out to every institution so that
maximum representation was sought and bias was minimized. Several
institutions indicated that their point person for leukemia has/have
filled out the survey. Thus, we believe that optimum attempts were made
to minimize the bias and optimize response rate. Other limitations
inherent to survey studies include the risk of recall bias and
misinterpretation of the questions.