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.