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Effect of pre-existing anti-PEG antibodies on PEG-ASNase
Figure 3. Box plots of PEG-asparaginase activities after the first dose of the drug. PEG-asparaginase (ASNase) activities were determined in patients of acute lym- phoblastic leukemia (ALL) cohort 1 on day 7±1 and day 14±1 after administration of the first dose of PEG-ASNase and grouped according to various cut-points for pre-existing anti-PEG IgG and IgM mean fluorescent intensity (MFI). The light gray boxes represent PEG-ASNase activities determined in patients with anti-PEG anti- body levels below the respective cut-point and the dark gray boxes represent PEG-ASNase activities determined in patients with anti-PEG antibody levels above the respective cut-point. The boxes represent the first and third quartiles, the lines in the box the medians, the whiskers the first quartile – (1.5 x the interquartile range between the first and third quartiles [IQR]) and the third quartile + (1.5 x IQR), and the dots the outliers. The dashed reference line represents the target PEG-ASNase activity of 100 U/L.
[CTCAE] grade 2) which were significantly associated with pre-existing anti-PEG IgG levels. Four of seven patients had pre-existing anti-PEG IgG (MFI ≥8) before their first PEG-ASNase dose (Table 3). No pre-existing anti- E. coli ASNase antibodies were detected in these patients. Four patients (2 with and 2 without pre-existing anti-PEG antibodies) were switched to Erwinia ASNase. Among the four patients with a first-exposure hypersensitivity reac- tion and pre-existing anti-PEG IgG no further boosts of anti-PEG IgG levels were observed. The two patients with pre-existing anti-PEG IgG, who continued on PEG- ASNase, completed the scheduled PEG-ASNase treatment without further signs of hypersensitivity. The relative risk of a hypersensitivity reaction upon first exposure to PEG- ASNase was 8 times higher for patients with anti-PEG IgG MFI ≥8 and 50 times higher for patients with anti-PEG IgG MFI ≥25 prior to their first PEG-ASNase (Table 3). This association was only observed for pre-existing anti-PEG IgG and not for pre-existing anti-PEG IgM.
Discussion
We detected a high prevalence of anti-PEG IgG (13.9%)
and IgM (29.1%) among children with primary ALL prior to their first PEG-ASNase.
Antibodies against PEG had already been detected in healthy volunteers of different ages and ethnicity and in patients who had never been treated with pegylated drugs before. The prevalence of anti-PEG antibodies in ALL- cohort 1 was within the range of reported prevalences (0.2 to 72%).14,18,19,22,26–30 However, it must be acknowledged that it is difficult to compare the prevalence between different studies when different methods and cut-points were used (Online Supplementary Tables S1 and S2).
The reported effects of pre-existing anti-PEG antibodies on the efficacy and tolerability of pegylated drugs vary.14,17– 19,31,32 Unexpectedly, the first administration of PEG-ASNase did not trigger the formation of further anti-PEG antibodies. Instead, anti-PEG antibody levels and their prevalence decreased, which was different from a typical hypersensi- tivity reaction to PEG-ASNase that developed after repeat- ed administration of PEG-ASNase.23,33–35 We also observed no increase in anti-PEG antibodies in the seven patients with hypersensitivity reaction at first exposure to PEG- ASNase.
Four of these patients had pre-existing anti-PEG IgG (MFI ≥8) (Table 3). This association was significant and the risk
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