Background: Rapid clearance of poly(ethylene glycol)-asparaginase (PEG-asparaginase) has been reported for up to one third of patients treated for acute lymphoblastic leukemia, potentially rendering their treatment ineffective [

Hempel G, Lanvers-Kaminsky C, Mueller, HJ, Würtwein G, Boos J.
Blood
.
2004
;
11
:
751A
]. Poly(ethylene glycol) is an inert, biocompatible synthetic polymer and has long been claimed to be non-immunogenic; several PEG-conjugated drugs are FDA approved and many other PEGylated agents are in development. However, we have previously reported a 25% occurrence of an antibody against PEG (anti-PEG) in healthy blood donors, which suggests that PEG is an immunogenic agent. [
Garratty G.
Trans Med Rev
.
2004
;
18
:
245
–56
].

Objective: To determine whether an anti-PEG could account for the rapid clearance of PEG-asparaginase.

Methods: This study re-analyzed stored serum samples from pediatric patients who were enrolled in the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster 2000 studies. Samples were selected to include 15 subjects who showed undetectable asparaginase activity after receiving PEG-asparaginase (Oncaspar®) and 13 with normal sustained levels of asparaginase activity after treatment with PEG-asparaginase. Sixteen subjects treated with unmodified asparaginase (Medac®) were also included, 8 with negligible asparaginase activity. Sera were tested for the presence of an anti-PEG using two techniques: 1) Serology, by agglutination of PEG-coated red blood cells; 2) Flow cytometry, by analysis of 10 μm PEG beads (Tentagel®-OH) pre-incubated with sera and stained for bound immunoglobulins with fluorescein-anti-human IgG and R-phycoerythrin-anti-human IgM. Testing for anti-PEG was performed in a blinded manner.

Results: For the PEG-asparaginase treated patients, of the 15 who showed undetectable asparaginase activity, 9 tested positive for anti-PEG by serology and 13 tested positive for anti-PEG by flow cytometry. All PEG-asparaginase treated patients with normal sustained asparaginase activity tested negative for anti-PEG. Four sera yielded somewhat unusual results: One weak IgM anti-PEG positive sample showed measurable asparaginase activity and three anti-PEG negative patients had low asparaginase activity, two of which were positive for anti-asparaginase. No relationship was observed between the presence of anti-PEG and serum asparaginase activity for the patients treated with unmodified asparaginase (Medac®).

Conclusions: The presence of anti-PEG was very closely associated with rapid clearance of PEG-asparaginase. Screening and monitoring for anti-PEG would allow for identification of a subset of patients for whom a modified dosing strategy or use of a non-PEGylated drug would be appropriate.

Topics:
antibodies, drug clearance, ethylene glycol, pegaspargase, asparaginase, acute lymphocytic leukemia, flow cytometry, immunoglobulin m, serologic tests, fluorescein

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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