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A. Khalil et al.
Table 2. Distribution of PEG-asparaginase activities below and above various thresholds among patients with and without preexisting anti-PEG antibodies.
Pre-existing anti-PEG IgG PEG-ASNase yes no
levels [MFI ≥ 8] [MFI < 8] <LLOQ 2 4
≥LLOQ 88 552
odds ratio (95% CI)
P-value 0.198
0.005 0.0005
P-value 1
0.22 0.045
adjusted P-value 0.535
0.085 0.002
adjusted P-value 0.535
0.476
0.021
< 100 U/L ≥ 100 U/L
< 400 U/L ≥ 400 U/L
PEG-ASNase levels
6 7 84 549
35 116 55 440
Pre-existing anti-PEG IgM yes no [MFI ≥ 2] [MFI < 2]
3.14 5.60 2.41
(0.57-17.4) (5.6-17.1) (1.51-3.86)
<LLOQ 2 4 ≥LLOQ 189 451
<100U/L 6 7 ≥ 100 U/L 185 448
<400U/L 55 96 ≥ 400 U/L 136 359
odds ratio (95% CI)
1.19 (0.22-6.57) 2.08 (0.69-6.62) 1.51 (1.03-2.22)
For each patient of ALL-cohort 1 only the lowest PEG-ASNase activities determined within 15 days after administration of 2500 U/m2 PEG-ASNase were evaluated. PEG-ASNase: polyethylene glycol asparaginase; MFI: mean fluorescence intensity; 95% CI: 95% confidence interval; LLOQ: lower limit of quantification; >: above threshold; <: below threshold.
for hypersensitivity reaction increased with increasing anti- PEG IgG levels prior to PEG-ASNase administration. A sig- nificant association between pre-existing anti-PEG antibod- ies and first-exposure hypersensitivity reaction was also documented in the RADAR phase IIb clinical trial, which evaluated pegnivacogin, a 2’-fluoropyrimidine-modified RNA aptamer, in patients with acute coronary syndrome.31 Among the six patients with the highest anti-PEG antibody levels prior to pegnivacogin administration, three suffered from a first-exposure hypersensitivity reaction. The first- exposure hypersensitivity reactions in the RADAR phase IIb clinical trial affected only 0.5% of patients but were con- sidered serious and led to early termination of the trial.31 In ALL-cohort 1 the first-exposure hypersensitivity reactions to PEG-ASNase were, however, only moderate (CTCAE grade 2).
Symptoms of moderate hypersensitivity reactions (CTCAE grade ≤2) and infusion-related adverse events are often difficult to distinguish.36 Typically, hypersensitivity reactions occur after re-challenge to the antigen and are associated with an increase in antibodies, which can per- sist in the blood for up to several weeks.23,37 Since this was not the case in patients with first-exposure hypersensitiv- ity reactions to PEG-ASNase and only moderate hypersen- sitivity reactions (CTCAE grade 2) occurred, one might conclude that pre-existing anti-PEG IgG simply predispose to mild hypersensitivity reactions for which re-challenge with PEG-ASNase may be possible. The two ALL patients withpre-existinganti-PEGIgGwhodevelopedfirst-expo- sure hypersensitivity reactions to PEG-ASNase and did not switch to Erwinia ASNase tolerated their subsequent PEG-ASNase administrations well.
Pre-existing anti-PEG antibodies are most likely trig- gered by repeated contact with PEG-containing products of daily life, such as cosmetics, pharmaceuticals and food. Depending on the nature of the PEG-containing com- pound, different immunological mechanisms are sup- posed to facilitate the anti-PEG antibody response.28,38,39 Experiments in nude mice showed that pegylated pro- teins induced the production of anti-PEG IgM in a T-cell-
dependent manner, whereas the induction of anti-PEG IgM by pegylated liposomes was T-cell independent.39,40 Furthermore, studies in animals indicated that these dif- ferent immunological processes may also lead to antibod- ies with different properties.40 Similar processes might also be feasible in humans and might explain why patients with pre-existing antibodies showed different antibody responses after their first PEG-ASNase dose than patients who developed a hypersensitivity reaction to the PEG-ASNase after repeated administrations and in whom the PEG covalently bound to the bacterial ASNase acted as a hapten.23,37 According to the “Consensus expert recommendations for identification and management of ASNase hypersensitivity and silent inactivation” discon- tinuation of treatment is recommended for grade ≥2 aller- gic reactions.24 Recently, the National Comprehensive Cancer Network clinical practice guidelines and other expert reviews on ASNase hypersensitivity recommend- ed switching of ASNase preparations only in the event of grade ≥3, severe or life-threatening allergic or anaphylac- tic reactions.36,41–43 In addition, because of the repeated shortage of Erwinia ASNase, various strategies were eval- uated in order to avoid or delay a switch to Erwinia ASNase as long as possible.36,44,45 Thus, PEG-ASNase was either generally administered under premedication or in the case of hypersensitivity reactions grade ≤2 under pre- medication at initially reduced infusion rates. In each case, PEG-ASNase activity was monitored to detect silent inactivation or premedication-masked hypersensitivity reactions.
Pre-existing anti-PEG antibodies reduced the PEG- ASNase activity levels as a function of concentration, but did not reduce the PEG-ASNase activity levels to such an extent that the criteria of silent inactivation were fulfilled. Silent inactivation (or subclinical hypersensitivity reac- tion) is characterized by the development of antibodies without overt symptoms of a hypersensitivity reac- tion.24,25 According to the “Consensus expert recommen- dations for identification and management of asparagi- nase hypersensitivity and silent inactivation” silent inacti-
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haematologica | 2022; 107(1)