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. ¹ 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. ² Yang et al. concluded that vincristine plus dexamethasone pulses might be omitted beyond one year of treatment for children with low-risk ALL. ² 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. ¹ 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. ³ Trough asparaginase activity levels of 100 U/L or greater appears to be a safe target level to ensure therapeutic benefit. ⁴ 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. ⁴ 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. ⁵ 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. ⁵ 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. ⁶ Wu et al. only studied the induction phase. ¹ 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. ⁶ 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. ³ Wu et al. suggested, however, that glutamine level might assist the prevention of anaphylaxis-related AEs. ¹ 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. ¹ 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. ⁷

To conclude, monitoring of asparaginase PK by means of TDM is a powerful tool. ⁷ This was confirmed by a recent expert panel discussion that agreed that TDM is useful to improve asparaginase efficacy. ⁸ Wu et al. did a great job to study difficult PK/PD parameters in children suffering from ALL, ¹ however new PK/PD challenges need to be explored to further improve individualized treatments.