Adverse Reactions to PEG and Erwinia Asparaginase and Correlation with Anti-Asparaginase Antibody Data and Survival in Children with Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group Study CCG 1961.
Authors: Dhall Girish , Jones Tamekia , Radvinsky David , Robison Nathan , Butturini Anna , Rubin Joan I , Gaynon Paul S. , Panosyan Eduard H , Avramis Ioannis A , Avramis Vassilios I , Ettinger Lawrence J. , Seibel Nita L. 
Published: October 2019

Abstract
Abstract 3077
Poster Board III-14
Asparaginase is an essential component of combination therapy for ALL and is derived from either Escherichia coli (Native ASNase) or Erwinia chrysanthemi (Erwinia ASNase). Allergic reaction is the most common toxicity of ASNase therapy. Some studies have shown no adverse impact of allergy to native ASNase on outcome. However, compared with native ASNase, in equal doses (“unit for unit” substitution), Erwinia ASNase has been associated with less toxicity and inferior survival in two large multi-institutional cooperative group trials. Pegylated Escherichia coli asparaginase (PEG) has a longer half-life compared to native ASNase and is presumed to be less immunogenic with equivalent efficacy at an appropriate dose and schedule. Between November 1996 and May 2002, 2057 eligible patients with newly diagnosed high-risk ALL were enrolled on Children's Oncology Group study, CCG-1961, and treated with a standard four-drug induction that included native ASNase. Rapid early responders (RER) randomized to stronger post-induction intensification (arms C &D) and all slow early responders (SER) were assigned 6 or 10 doses of PEG (2500 IU/m2/dose) post-induction (n=1157). Patients received native ASNase if PEG was not available. Those with adverse reactions to PEG received Erwinia ASNase (10,000 IU/m2 qod x 6 during consolidation and delayed intensification and 25000 IU/m2 during interim maintenance per single dose of PEG). Antibody titers were collected on a subset of patients pre-consolidation and through all phases. Reaction incidence and event-free survival (EFS) in patients who received PEG versus Erwinia ASNase and in patients with negative versus positive antibody titer were compared among patients assigned to PEG containing regimens. Likelihood of allergic reactions was similar with PEG, native ASNase, and Erwinia during all phases with the exception of Interim Maintenance 1 (IM1). Reactions were less likely with Erwinia (n=235) than with Native ASNase (n=87; odds ratio [OR] = 0.23, p <0.0001) and PEG (n=619; OR = 0.32, p <0.0001) during IM1. Antibody titers collected on 600 patients on or before the first day of consolidation were then correlated with reaction incidence to PEG during subsequent phases. Of the 340 patients with complete data, 97 (28.5%) patients had a positive antibody (titer >1.1) and 243 (71.5%) had a negative antibody (titer ≤1.1). Patients with a positive antibody pre-consolidation were more likely to have an allergic reaction to PEG during consolidation or a subsequent phase than patients who had a negative antibody (OR = 2.41, p <0.001). When we correlated event-free survival (EFS) in 368 patients with antibody titer pre-consolidation, we found no significant difference in the 5-year EFS between patients with a negative (n=263) versus positive (n=105) antibody titer (5-year EFS = 80%, SE = 0.03 versus 5-year EFS = 77.7%, SE = 0.04, p=0.68). To compare the EFS of patients receiving either PEG or Erwinia ASNase, we selected patients who did not have any allergic reaction to PEG and continued to receive PEG throughout their treatment (n=235) and patients who had an allergic reaction to PEG during consolidation and received Erwinia ASNase for all subsequent doses without developing hypersensitivity (n=118). The two groups were similar with regard to sex, race, WBC count at diagnosis, response to therapy (RER and SER patients in each group) and ALL phenotype by univariate analysis. We found no significant difference in 5-year EFS between the two groups (5-year EFS = 80.8%, SE = 0.03 versus 5-year EFS = 81.6%, SE = 0.04, respectively, p=0.66). To conclude, Erwinia ASNase was associated with less toxicity when compared to both PEG and native ASNase during IM1. A positive antibody titer prior to consolidation did not alter the 5-year EFS but was associated with an increased incidence of clinical allergy to PEG during subsequent phases. We found no effect on EFS when Erwinia ASNase was substituted for PEG after an allergic reaction.

Disclosures
Gaynon: Enzon: Speakers Bureau.