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Randomized Controlled Trial
. 2014 Dec 1;32(34):3874-82.
doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27.

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

Anne L Angiolillo  1 , Reuven J Schore  2 , Meenakshi Devidas  2 , Michael J Borowitz  2 , Andrew J Carroll  2 , Julie M Gastier-Foster  2 , Nyla A Heerema  2 , Taha Keilani  2 , Ashley R Lane  2 , Mignon L Loh  2 , Gregory H Reaman  2 , Peter C Adamson  2 , Brent Wood  2 , Charlotte Wood  2 , Hao W Zheng  2 , Elizabeth A Raetz  2 , Naomi J Winick  2 , William L Carroll  2 , Stephen P Hunger  2
Affiliations
Randomized Controlled Trial

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

Anne L Angiolillo et al. J Clin Oncol. .

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/m(2) (SC-PEG2500; n = 42) versus SS-PEG 2,500 IU/m(2) (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.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
CONSORT diagram for Children's Oncology Group AALL07P4. PK, pharmacokinetic; SC-PEG, calaspargase pegol; SS-PEG, pegaspargase.
Fig 2.
Fig 2.
Mean plasma asparaginase activity versus asparagine concentration by treatment group over time during (A) induction (IND) and (B) consolidation (CON), and (C) mean CSF asparagine concentration by treatment group over time during IND and CON. SC-PEG, calaspargase pegol; SS-PEG, pegaspargase.
Fig 3.
Fig 3.
Plasma asparaginase activity presented as percentage of pharmacokinetically evaluable patients with asparaginase activity ≥ 100 and ≥ 400 mIU/mL by treatment group over time during (A) induction and (B) consolidation. SC-PEG, calaspargase pegol; SS-PEG, pegaspargase. (*) P < .001. (†) P = .006. (‡) P = .008. (§) P = .002.
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