Should We Use a Desensitization Protocol In Acute Lymphoblastic Leukemia Patients With Silent Inactivation Of Pegasparaginase?
Authors: Tong Wing H. , Pieters Rob , Tissing Wim J , van der Sluis Inge M. 
Published: October 2019

Abstract

Purpose
Previous studies have shown that children with silent inactivation of asparaginase had poorer outcomes as they were not switched to another asparaginase preparation that retained its activity. Recently, a case report was published that described the successful use of desensitization courses in a patient with severe hypersensitivity reaction to asparaginase. We analyzed whether continuation of asparaginase in case of silent inactivation may result in desensitization, disappearance of asparaginase antibodies (AAA) and recovery of asparaginase activity levels in children with newly diagnosed acute lymphoblastic leukemia (ALL).

Patients and Methods
Children who received intensified PEGasparaginase or Erwinia asparaginase for 30 weeks according to the intensification phase of the Dutch Childhood Oncology Group-ALL-10 medium-risk protocol were studied. All children had received native E.coli asparaginase in induction and all asparaginase preparations were administered intravenously in one hour. AAA against native E.coli asparaginase (Coli-AAA), PEGasparaginase (PEG-AAA), and Erwinia asparaginase (Erwinia-AAA) and PEGasparaginase and Erwiniaasparaginase activity levels were analyzed in serum.

Results
7/89 patients had silent inactivation of PEGasparaginase. Two were detected by real-time asparaginase activity measurements and were switched to Erwinia asparaginase. Five patients continued PEGasparaginase because no real-time asparaginase measurements were available at the starting phase of our drug monitoring program. Those patients with silent inactivation were, therefore, not recognized in time. PEGasparaginase activity levels recovered in all 5 patients after 2-7 PEGasparaginase infusions. In all 5 patients, Coli-AAA were present at start of the intensification phase which declined over time coinciding with the rise of PEGasparaginase activity levels. PEG-AAA were absent at the start of intensification but also increased after 1-2 doses of PEGasparaginase, and declined thereafter also coinciding with recovery of the PEGasparaginase activity levels.
29% of the PEGasparaginase patients without an allergy and without silent inactivation were positive for Coli-AAA. Also in this group, the Coli-AAA gradually decreased to undetectable levels after 5 PEGasparaginase courses.
In a different cohort of 59 patients treated with Erwinia asparaginase, there were no cases of silent inactivation and two developed allergic reactions. In 50% of the non-allergic patients, the Erwinia-AAA were absent at start of therapy, gradually increased and decreased to absent baseline values during 30 weeks of Erwiniaasparaginase therapy.

Conclusion
This unintended desensitization program applied in five patients with silent inactivation of PEGasparaginase leads to recovery of PEGasparaginase activity levels. However, this takes an unpredictable and sometimes long time period. Therefore, we do not advise such desensitization approaches, but recommend switching to Erwinia asparaginase. A significant proportion of patients treated for prolonged period with PEGasparaginase or Erwinia asparaginase develops antibodies without influencing asparaginase activity levels that disappear with continued use of the same asparaginase product.

Disclosures:
No relevant conflicts of interest to declare.