Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Abstract

Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (7s.d.) CSF asparagine (0.2970.63, n ¼ 9) than those who received PEG (0.7770.82, n ¼ 4) (P ¼ 0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.

Anti–Escherichia coli asparaginase antibody levels determine the activity of second-line treatment with pegylated E coli asparaginase: a retrospective analysis within the ALL-BFM trials

“…on April 27, 2019. by guest www.bloodjournal.org From reported that the administration of pegylated E coli ASE, compared with native E coli ASE or Erwinia ASE, after an allergic reaction to native E coli ASE or in case of detectable Abs against the native form did not increase the depletion of asparagine. 22 In addition, Asselin et al 23 determined an increased clearance of pegylated E coli ASE after allergic reactions to native E coli ASE. However, drug monitoring within the ALL-BFM trials provided evidence of sufficient ASE activity in numerous patients when pegylated E coli ASE was given as a second-line treatment after allergic reactions to E coli ASE.…”

A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug l-asparaginase

“…Why this happens is not well understood. Florid hypersensitivity reactions can occur, necessitating withdrawal of the drug, though not all patients with hypersensitivity develop neutralizing antibodies and not all patients who develop neutralizing antibodies exhibit hypersensitivity (12,13). Again, the reason why some patients develop allergy to l-asparaginase remains unknown.…”

Semi-permeable coatings fabricated from comb-polymers efficiently protect proteins in vivo

“…One protein that falls into this category is L-asparaginase (ASNase), an enzyme that is used for treating acute lymphoblastic leukaemia. This protein was one of the first to be modified with mPEG because of its propensity to cause severe hypersensitivity reactions (up to 20-30% of patients) 13 or suffer from 'silent inactivation' by the neutralizing or opsonizing antibodies 14,15 . Modification of ASNase with mPEG in part overcomes these problems 16 , however, a key problem is that antibody responses against mPEG-ASNase continue to occur in B18% of patients [17][18][19] .…”