Optimizing pegaspargase therapy in patients with hypersensitivity reactions

Dear Editor, Pegaspargase is the more commonly used form of asparaginase [1]. It is an immunogenic compound and can cause reactions ranging from skin rash and nausea to life threatening anaphylaxis in up to 20–30% of the patients [2,3]. The reactions occur early in therapy, more commonly after two doses. Some protocols, including the Children’s Oncology Group (COG), recommend switching to Erwinia asparaginase in case of a grade 2 hypersensitivity reaction, others do in case of grade 3 and above hypersensitivity reactions [4]. However, Erwinia has challenges with accessibility, and is significantly more expensive than pegaspargase [5]. This often leads to skipped doses of asparaginase {especially in lowand middleincome countries (LMIC)} or causing a delay in the administration by several weeks to months, which has been shown to result in inferior outcomes in leukemia patients [6]. The clinical dilemma of when it is appropriate to switch asparaginase products often stems from both a lack of consistency in classification of the reactions and restricted global availability and affordability of asparaginase activity monitoring that can result in unnecessary switching of asparaginase products. Desensitization can be an effective way for optimizing pegaspargase therapy in children with allergic reactions. A safe and effective desensitization protocol that can be applied globally could reduce the need to discontinue asparaginase therapy. With the global shortage of Erwinia, a desensitization protocol was introduced at our center in 2020 to manage pediatric patients with reactions to pegaspargase. We performed a review of patients who received pegaspargase by the desensitization approach from June 2020 until May of 2021 after Institutional Research Ethics Board approval. Patients who received less than 50% of the intended dose of pegaspargase due to a hypersensitivity reaction and who failed re-challenge were offered the desensitization protocol. Patients who received more than 50% of the dose and reacted with therapeutic asparaginase levels and failed re-challenge were offered the desensitization protocol for subsequent doses. Initial desensitization was performed in the intensive care unit and subsequent doses were given on the inpatient unit. Therapeutic drug monitoring (TDM) was performed to establish drug effectiveness. The day 1 and 2 drug activity levels help in early identification of patients that need to be switched to Erwinia and Day 7 and 14 levels were used to establish therapeutic efficiency of desensitization. Supplemental Table 1 describes the protocol. The administration of pegaspargase at our center includes universal premedication with histamine blockers, antiemetics and an antipyretic. We also administer the drug intravenously over 2 h with 20% of the dose infused over the first hour and remaining 80% over the second hour. Five patients received the desensitization protocol for 12 doses of pegaspargase. All 5 patients had previously developed grade 3 allergic reactions as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5 with pegaspargase therapy and received epinephrine during management of the reaction (Table 1). Based on our modified allergic grading criteria (Supplemental Table 1), 4 patients had moderate hypersensitivity after dose #2 and 1 patient had severe hypersensitivity after dose #3 with hypotension requiring fluid resuscitation. Two of the five patients received Erwinia asparaginase prior to shifting to the desensitization protocol. The median time between the hypersensitivity reaction and administration of the desensitization in the remaining three patients was 10 days (range 3–10 days). With the first dose, 4 patients received full dose of pegaspargase, and one received 80% of the first dose. The only documented adverse reaction was a grade 2 skin rash in one patient, which was managed with temporary cessation of the infusion and intravenous antihistamine medication. The infusion was restarted; however, the total duration of infusion was prolonged, resulting in only 80% of the dose being administered. One patient had a sub-therapeutic drug activity level of 0.005 IU/mL on day 2 and