Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Study AALL07P4

Abstract

Purpose Asparaginase is a critical agent used to treat acute lymphoblastic leukemia (ALL). Pegaspargase (SS-PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker, is the first-line asparaginase product used in Children's Oncology Group (COG) ALL trials. Calaspargase pegol (SC-PEG) replaces the SS linker in SS-PEG with a succinimidyl carbamate linker, creating a more stable molecule. COG AALL07P4 was designed to determine the pharmacokinetic and pharmacodynamic comparability of SC-PEG to SS-PEG in patients with newly diagnosed high-risk (HR) B-cell ALL. Patients and Methods A total of 165 evaluable patients were randomly assigned at a 2:1 ratio to receive SC-PEG at 2,100 (SC-PEG2100; n = 69) or 2,500 IU/m2 (SC-PEG2500; n = 42) versus SS-PEG 2,500 IU/m2 (SS-PEG2500; n = 54) as part of an otherwise identical chemotherapy regimen. The groups were similar demographically, except more female patients received SC-PEG2500. Results The mean half-life of plasma asparaginase activity for both SC-PEG doses was approximately 2.5× longer than that of SS-PEG2500. The total systemic exposure, as defined by induction area under the curve from time 0 to 25 days, was greater with SC-PEG2500 than with SS-PEG2500 or SC-PEG2100. The proportion of patients with plasma asparaginase activity ≥ 100 mIU/mL and ≥ 400 mIU/mL was higher in patients who received SC-PEG as compared with SS-PEG2500. After one dose of pegylated asparaginase on induction day 4, plasma asparagine was undetectable for 11 days for SS-PEG2500 and 18 days for both SC-PEG groups. Conclusion SC-PEG2500 achieves a significantly longer period of asparaginase activity above defined thresholds and asparagine depletion compared with SS-PEG2500 and has a comparable toxicity profile in children with HR B-cell ALL.

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

“…[16] Recent pharmacokinetic reports of IV PEG-asparaginase in 43 newly diagnosed patients with high-risk B-ALL identified a mean half-life of 5.29 days (standard deviation, 1.13 days) during induction therapy, nearly identical to IM PEG-asparaginase. [21] Similarly, Silverman et al [22] reported no discernable differences in the time course of serum enzymatic activity after IV administration of PEG-asparaginase when compared with previous reports of IM administration. [19,23] The longer half-life of PEG-asparaginase allows for patients to maintain therapeutic levels of asparaginase activity (> 0.1 IU/mL) for a greater duration following a single dose.…”

“…[37,100] One recent study measuring asparaginase activity levels and plasma asparagine concentrations found that asparagine was completely depleted at higher asparaginase activity levels, but began to rebound once plasma asparaginase activity declined to <0.4 IU/mL. [21] Another modeling study in adult ALL patients found that PEG-asparaginase activity levels of 0.2 IU/mL were required to achieve 90% asparagine depletion. [101] Since suboptimal depletion has been associated with poor outcomes, caution should be exercised in continuing patients on a treatment that does not sufficiently deplete their asparagine.…”

Severe pegaspargase hypersensitivity reaction rates (grade ≥3) with intravenous infusion vs. intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children’s oncology group (COG) clinical trials

“…However, these patients were included for comparisons for pegaspargase grade ≥3 HSR occurring after dose #2 or #3 (during Consolidation) to provide a more uniform group of HR B-ALL and T-ALL/LL patients receiving similar therapy. These analyses did not include HR and Very High-Risk (VHR) patients with B-ALL who enrolled on AALL1131 and were randomized to experimental arms 1 or 2, or patients who were enrolled on AALL07P4 [14] and randomized to receive EZN-2285 (calaspargase pegol; SC-PEG). The dose of pegaspargase across all six trials was 2500 IU/m 2 with no dose capping allowed on protocol with an infusion time of 1–2 h recommended for intravenous administration.…”

“…In all of these trials except AALL07P4, only grade ≥3 toxicity data were collected by the COG and therefore only grade ≥3 HSR are reported in this analysis. AALL07P4 assessed all grades (including grade 1 and 2) of toxicity because the trial randomized patients to receive either pegaspargase or a new PEGylated formulation of asparaginase (calaspargase pegol; SC-PEG) that used a succinimidyl carbamate (SC) linker rather than the succinimidyl succinate linker used in pegaspargase [14]. The second and third doses of pegaspargase accounted for 71% of all HSRs and thus were primarily used to assess grade ≥3 HSR rates (Figure 1).…”

Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation

“…29 However, based on the literature to date, we consider that a nadir serum asparaginase activity level of ≥ 0.1 IU/mL appears to be an appropriate and safe target level, because complete depletion is observed less consistently with asparaginase activity levels below this cut-off. In addition, in the absence of further data, we consider a desirable level of activity for patients receiving pegaspargase to be defined as ≥ 0.1 IU/mL at 14 days postadministration.…”