Erwinia Asparaginase Safety and Feasibility during Therapy for Acute Lymphoblastic Leukemia in Adult Patients with Pegaspargase Hypersensitivity or Severe Toxicity
Authors: Horvat Troy Z , Pecoraro Joshua J , Daley Ryan J , Buie Larry W , Douer Dan 
Published: November 2019

Abstract
Introduction: Severe pegaspargase hypersensitivity during first-line therapy for acute lymphoblastic leukemia (ALL) occurs in 1.8-5.9% of patients (Oncaspar [package insert]; Douer D, et al. J Clin Oncol 2014;32:905-911). Erwinia asparaginase is the preferred therapeutic alternative as it retains excellent activity in patients with Escherichia coli asparaginase or pegaspargase antibodies (Willer A, et al. Blood 2011;118:5774-82; Plourde PV, et al. Pediatr Blood Cancer 2014;61:1232-38; Salzer WL, et al. Blood 2013;122:507-14; Zalewska-Szewczyk B, et al. Clin Exp Med 2009;9:113-16). Furthermore, pegaspargase desensitization may not prevent recurrence of severe allergy (Sahiner UM, et al. Pediatr Int 2013;55:531-33). The risk for allergy and other common asparaginase-related adverse effects exists with Erwinia asparaginase, however most data is from pediatric reports. The aim of this study was to assess the safety and feasibility of using Erwinia asparaginase in adult ALL patients with previous pegaspargase hypersensitivity or intolerance.
Methods: This is a single-center retrospective analysis of eight adult ALL patients who received Erwinia asparaginase after intolerance to pegaspargase between November 2011 and July 2015. Toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0. The Memorial Sloan Kettering Investigational Review Board granted an exemption from IRB review.
Results: The eight patients received a total of 29 cycles (median 3 cycles each, range 1-6) as part of various pediatric-inspired chemotherapy regimens. Each cycle consisted of Erwinia asparaginase 25,000 units/m2 intramuscularly every 48 hours (either including or excluding weekends). Corticosteroid premedication was given with 52 of 170 total Erwinia asparaginase doses. The median age was 33 years (range 23-72), 7 (87.5%) were males, 75% had B-cell ALL, and 25% had T-cell ALL. Seven patients received Erwinia asparaginase while in first complete remission (CR1) and only one as part of second-line therapy. Patients received a median of 2 prior doses of pegaspargase (range 1-4) before switching to Erwinia asparaginase for either grade 3/4 anaphylaxis (n=6), urticaria/pruritus (n=1), or grade 4 hyperbilirubinemia (n=1). Six patients received all intended cycles, 1 patient was lost to follow up after 1 cycle, and 1 patient was still receiving treatment at the time of analysis. No hypersensitivity reactions occurred and no patient developed arterial or venous thrombosis. Laboratory adverse effects are reported in table 1. One patient died from disease (the 1 patient that received Erwinia asparaginase as part of second-line therapy), 1 patient died in a motor vehicle accident while in first remission, and six patients are still alive and in first remission at 7.5-29.6 months from diagnosis. No morphologic relapses have occurred in patients in first remission (n=7) at a follow up of 4.9-26.4 months after switching to Erwinia asparaginase.
Conclusions: Replacing pegaspargase with Erwinia asparaginase after hypersensitivity allowed all patients to continue asparaginase therapy without hypersensitivity. Adverse effects with Erwinia asparaginase were limited to laboratory abnormalities of minimal clinical consequence. In contrast to the known high rate of hepatoxicity in adults treated with pegaspargase, no high grade liver toxicity was seen. In light of the critical role of asparaginase in ALL therapy, our preliminary observations suggest that asparagine depletion with Erwinia asparaginase can proceed as scheduled despite pegaspargase intolerance. Within our small cohort undergoing first-line therapy, relapse did not occur after transitioning to this therapeutic alternative.
Table 1. Laboratory abnormalities by grade Grade 1 Grade 2 Grade 3 Grade 4 AST 7 0 0 0 ALT 7 2 0 0 TBILI 1 0 0 0 Amylase 2 0 0 0 Lipase 1 1 0 0 Triglycerides 3 4 3 1 Fibrinogen 2 6 1 0 Total 23 13 4 1 *Laboratory abnormalities were counted per event, not per patient

Disclosures
Douer: Gilead: Consultancy.