Preliminary Results Of a Pharmacokinetic Study Of Intravenous Asparaginase Erwinia Chrysanthemi Following Allergy To E Coli-Derived Asparaginase In Children, Adolescents, and Young Adults With Acute Lymphoblastic Leukemia Or Lymphoblastic Lymphoma
Authors: Vrooman Lynda M. , Kirov Ivan I. , Dreyer Zoann E. , Kelly Michael , Hijiya Nobuko , Brown Patrick , Drachtman Richard A. , Messinger Yoav H , Ritchey A. Kim , Hale Gregory A. , Maloney Kelly , Plourde Paul V. , Silverman Lewis B. 
Published: October 2019

Abstract

Background
Asparaginase is an important component of therapy for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). However, up to 30% of patients (pts) develop an allergy to Escherichia coli (E coli)–derived asparaginase. In those pts, Erwinia asparaginase (Erwinia), an antigenically distinct preparation derived from Erwinia chrysanthemi, can be used. Although Erwinia is typically administered intramuscularly (IM), intravenous (IV) asparaginase would offer a more convenient, less painful administration route. In an open-label, single-arm, multicenter, pharmacokinetic (PK) study, we evaluated IV administration of Erwinia in children and adolescents with ALL who developed hypersensitivity to E coli–derived asparaginase.

Methods
Pts (aged ≥1 to ≤30 years) with ALL or LBL who developed hypersensitivity (grade ≥2) to E coli–derived asparaginase were eligible for enrollment. Pts received Erwinia IV, 25,000 IU/m2/dose, on a Monday/Wednesday/Friday (M/W/F) schedule for 2 consecutive weeks (6 doses=1 cycle) for each dose of pegaspargase remaining in the original treatment plan. All other chemotherapy was continued per the original treatment plan. Blood samples were collected during the 1st treatment cycle, including predose, 5 min, 48 hrs and 72 hrs postdose. The primary study objective was to determine the proportion of pts who achieved nadir serum asparaginase activity (NSAA) ≥0.1 IU/mL, which has been associated with complete asparagine depletion, at 48 hrs after dose 5 in cycle 1. Secondary objectives included determining the proportion of pts who achieved NSAA ≥0.1 IU/mL at 72 hrs after dose 6 in cycle 1 and the incidence of asparaginase-related toxicities. Only pts who completed 1 cycle of Erwinia were considered evaluable for NSAA assessment.

Results
Between November 2012 and June 2013, 30 pts were enrolled from 10 centers; 26 pts completed cycle 1. Twenty-three pts were evaluable for the primary NSAA endpoint (3 pts were not evaluable; 2 for PK data collected outside the protocol-specified window and 1 for nonadherence to the dosing schedule). Median age was 6.5 years (1-17 years), 63% were male, and 83% Caucasian. Predose NSAA levels were below the limit of quantification (defined as 0.0129 IU/mL) for nearly all (91%) pts. Of the 23 evaluable pts who completed cycle 1, 19 (83%) achieved NSAA levels ≥0.1 IU/mL at 48 hrs postdose 5, with mean ±SD NSAA 0.32 ±0.23 (Table 1). At 72 hrs postdose 6, 9 pts (45%) achieved NSAA levels ≥0.1 IU/mL (mean ±SD 0.088 ±0.076).
Four pts discontinued Erwinia treatment before completing cycle 1; 3 for hypersensitivity and 1 for pancreatitis. The toxicity analysis included all 30 enrolled pts. The most common asparaginase-related toxicities reported during cycle 1 were: hypersensitivity (23% of pts), vomiting (20%), nausea (20%), and hyperglycemia (13%). Pancreatitis occurred in 3% and thrombosis in 3% of pts. One pt experienced a transient ischemic attack. The most common grade 3 or 4 adverse event was febrile neutropenia (7%). There were no deaths.

Conclusions
The majority (83%) of children and adolescents with ALL or LBL receiving Erwinia IV at 25,000 IU/m2/dose on a M/W/F schedule, achieved NSAA ≥0.1 IU/mL at 48 hrs postdose 5 (considered the therapeutic goal); however the majority did not achieve this goal at 72 hrs post Erwinia dose 6. With IV administration, asparaginase-related toxicities appeared to be consistent with previous reports in children treated with IM Erwinia. Based on these results, we are now evaluating IV Erwinia at 25,000 IU/m2/dose administered every 48 hrs rather than on a M/W/F schedule.
This study was funded by Jazz Pharmaceuticals plc.

Disclosures:
Off Label Use: ERWINAZE (asparaginase Erwinia chrysanthemi) is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL)who have developed hypersensitivity to E. coli-derived asparaginase. The recommended dose is 25,000 International Units/m2 administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase. Hijiya:Jazz Pharmaceuticals: Consultancy. Brown:Jazz Pharmaceuticals: advisory board Other. Drachtman:Jazz Pharmaceuticals: Honoraria. Messinger:Jazz Pharmaceuticals: Advisory Board Other. Plourde:Jazz Pharmaqceuticals: Employee of Jazz Pharmaceuticals, Inc, who in the course of this emplyment has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc Other, Employment. Silverman:Enzon Pharmaceuticals: Consultancy; Sigma Tau Pharmaceuticals: Advisory Board, Advisory Board Other; EUSA Pharma: Advisory Board Other.