Pegylated E. coli Asparaginase Desensitization: An Effective and Feasible Option for Pediatric Patients with Acute Lymphoblastic Leukemia Who Have Developed Hypersensitivity to Pegaspargase in the Absence of Asparaginase Erwinia Chrysanthemi availability

Abstract Background: L-asparaginase makes up a critical component of multi-agent chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL), the most common pediatric malignancy. Currently, there are two asparaginase preparations approved by the US Food and Drug Administration, available for use in the United States. These are pegaspargase, a PEGylated form of asparaginase, having polyethylene glycol [PEG] attached to native Escherichia coli asparaginase, and asparaginase Erwinia chrysanthemi (Erwinaze®), derived from cultures of Erwinia chrysanthemi. Hypersensitivity reactions are the most common toxicity observed, reported in up to 60% of patients treated with various schedules of native E. coli asparaginase. Due to the short half-life of Erwinaze®, multiple doses are required to be given to replace one dose of the PEGylated form. The United States market recently experienced a nationwide shortage of Erwinaze®. During this shortage, many patients who previously developed hypersensitivity to pegaspargase have been unable to receive asparaginase therapy. Current options recommended by consortium groups during this shortage recommended omission of all asparaginase therapy in these patients' regimens, which may lead to a greater risk for relapse, and for those who have relapsed, a greater risk for re-induction failure. Treatment: A 13 step rapid desensitization protocol utilizing chemotherapy desensitization protocols published by Castells et al, was developed to administer pegaspargase to five patients with ALL in various stages of therapy. Pegaspargase was administered using a serial dilution protocol infused over 6 hours in the pediatric intensive care unit. Patients were pre-medicated with steroids, diphenhydramine and acetaminophen. Asparginase levels were obtained between days 4-7 and 10-14, to ensure patients had sustained levels of asparginase activity. Cases: Patient #1: 7 year old female with late relapse of B ALL , experienced immediate hypersensitivity to second dose of pegaspargase as well as to subsequent Erwinaze® during upfront therapy. She received two courses of pegaspargase via desensitization protocol during re-induction at relapse tolerated it well with sustained asparginase activity. Patient #2: 18 year-old female with very high risk B ALL, experienced immediate hypersensitivity to third dose of pegaspargase as well as to subsequent Erwinaze®. She received 2 doses of pegaspargase via desensitization protocol during interim maintenance II, tolerated it well with sustained asparginase activity. Patient #3: 7 year old male with late relapse of B ALL, experienced immediate hypersensitivity to third dose of pegaspargase during upfront therapy. At relapse, Erwinaze® was unavailable due to nationwide shortages. He received 2 doses of pegaspargase via desensitization protocol, tolerated it well with sustained asparginase activity. Patient #4: 3 year old male with intermediate risk T ALL, experienced immediate hypersensitivity to second dose of pegaspargase as well as subsequent Erwinaze®. He received one dose of pegaspargase via desensitization protocol during interim maintenance, tolerated it well with sustained asparginase activity. Patient #5: 15 year old male with intermediate risk T ALL, experienced immediate hypersensitivity to second dose of pegaspargase. Due to shortage of Erwinaze®, he received one dose of pegaspargase via desensitization protocol during delayed intensification and tolerated it well, but did not have sustained asparginase activity. Thus, he did not receive any further pegaspargase doses. Results: None of the five patients developed hypersensitivity reactions during their desensitization protocols. Three patients had sustained activity, one patient showed early therapeutic levels, but low activity at day 14 consistent with accelerated clearance, and one patient did not achieve therapeutic levels, consistent with neutralizing antibody. Cost of one desensitization may be more cost effective than that associated with six doses of Erwinaze®. Conclusions: Pegaspargase can be safely administered to patients who have had a prior hypersensitivity to pegaspargase using a standard rapid desensitization protocol. Per our experience, the desensitization protocol is safe and effective in maintaining sustained levels of asparaginase activity, and could be cost effective when Erwinaze® is not available. Disclosures No relevant conflicts of interest to declare.