Comment on "Correlation of L-asp Activity, Anti-L-asp Antibody, asn and gln with Adverse Events Especially Anaphylaxis Risks in PEG-asp-Contained Regime Treated Pediatric ALL".

Dear Editor

I have read with great interest the publication by Wu et al. In the context of the Chinese Children's Cancer Group (CCCG)-ALL-2015 protocol, they studied the plasma L-asp activity/anti-L-asp antibody/asparagine/glutamine levels of 91 pediatric ALL patients who underwent PEG-asp-contained treatment on the seventh day after drug administration. Very recently, this CCCG-ALL-2015 protocol was used in an open-label, multicenter, randomized, phase 3, non-inferiority trial which involved twenty major medical centers across China. Yang et al. concluded that vincristine plus dexamethasone pulses might be omitted beyond one year of treatment for children with low-risk ALL. Wu et al. suggested that the measurement of L-asp activity/anti-L-asp antibody/asparagine/glutamine levels might assist the prevention of anaphylaxis-related AEs in pediatric ALL patients who underwent PEG-asp-contained treatment. Although this clinical study is of interest, some important questions can be raised, which I address below.

Wu et al. measured the PK/PD parameters during PEG-asp-contained treatment on day seven after administration. At that moment, no trough activity levels were monitored. Trough asparaginase activity levels of 100 U/L or greater appears to be a safe target level to ensure therapeutic benefit. Why did Wu et al. choose to use the peak levels on day 7 of PEGasparaginase?

Furthermore, anti-asparaginase antibodies and asparagine measurements are not indicated for clinical decision making outside the context of a clinical trial. Wu et al. studied anti-L-asp antibody, however, recent publications showed that not anti-L-asp antibody, but PEG is the major antigen that causes allergic reactions. Liu et al. concluded that anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEGasparaginase as well as in identifying patients who are most likely to experience failure with rechallenge. Similar finding was found by the Dutch researchers, namely that anti-asparaginase antibodies were detected in only 11% during induction (of their DCOG ALL-11 protocol), but 94% during intensification. Wu et al. only studied the induction phase. Kloos et al. concluded, however, that anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Of interest, these authors suggest that switching to native Escherichia coli asparaginase would be an option for adequate treatment. Do Wu and colleagues also have data on anti-PEG-ASP? If not, why did the authors only focus on anti-L-asp antibody?

Previously, it was published that no glutamine depletion was seen during PEGasparaginase therapy. Wu et al. suggested, however, that glutamine level might assist the prevention of anaphylaxis-related AEs. It is remarkable that these authors did find glutamine depletion, how could this phenomenon be explained? What was the role and the influence of day 7 post-infusion measurement on the glutamine level in this clinical study?

Finally, Wu et al. stated that for patients with plasma drug activity < 100 U/L, it was suggested to switch from PEGasparaginase to Erwinia asparaginase. These authors found that seven patients had anaphylaxis. These patients were switched to Erwinia asparaginase, were the data available after the switch on these parameters: L-asp activity/anti-L-asp antibody/asparagine/glutamine levels? This is particularly of interest as the number of patients switching to Erwinia asparaginase is currently limited.

To conclude, monitoring of asparaginase PK by means of TDM is a powerful tool. This was confirmed by a recent expert panel discussion that agreed that TDM is useful to improve asparaginase efficacy. Wu et al. did a great job to study difficult PK/PD parameters in children suffering from ALL, however new PK/PD challenges need to be explored to further improve individualized treatments.