Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegaspargase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: A report from the Children's Oncology Group

Abstract

Background Erwinia asparaginase is a Food and Drug Administration approved agent for the treatment of acute lymphoblastic leukemia (ALL) for patients who develop hypersensitivity to Escherichia coli derived asparaginases. Erwinia asparaginase is efficacious, but has a short half-life, requiring six doses to replace one dose of the most commonly used first-line asparaginase, pegaspargase, a polyethylene glycol (PEG) conjugated E. coli asparaginase. Pegcristantaspase, a recombinant PEGylated Erwinia asparaginase with improved pharmacokinetics, was developed for patients with hypersensitivity to pegaspargase. Here, we report a series of patients treated on a pediatric phase 2 trial of pegcrisantaspase. Procedure Pediatric patients with ALL or lymphoblastic lymphoma and hypersensitivity to pegaspargase enrolled on Children's Oncology Group trial AALL1421 (Jazz 13-011) and received intravenous pegcrisantaspase. Serum asparaginase activity (SAA) was monitored before and after dosing; immunogenicity assays were performed for antiasparaginase and anti-PEG antibodies and complement activation was evaluated. Results Three of the four treated patients experienced hypersensitivity to pegcrisantaspase manifested as clinical hypersensitivity reactions or rapid clearance of SAA. Immunogenicity assays demonstrated the presence of anti-PEG immunoglobulin G antibodies in all three hypersensitive patients, indicating a PEG-mediated immune response. Conclusions This small series of patients, nonetheless, provides data, suggesting preexisting immunogenicity against the PEG moiety of pegaspargase and poses the question as to whether PEGylation may be an effective strategy to optimize Erwinia asparaginase administration. Further study of larger cohorts is needed to determine the incidence of preexisting antibodies against PEG-mediated hypersensitivity to pegaspargase.

Both IgM and IgG Antibodies against Polyethylene Glycol Can Alter the Biological Activity of Methoxy Polyethylene Glycol-Epoetin Beta in Mice

“…PEG was long considered to be nonimmunogenic, but recent reports show that anti-PEG antibodies can be induced by injection of some types of pegylated liposomes or proteins in clinical trials [6][7][8][9][10][11][12][13][14] and animal studies [15][16][17][18][19][20][21][22][23][24]. Although anti-PEG antibodies do not appear to be induced when most pegylated human proteins are administered to patients, a large proportion of the general population never exposed to pegylated drugs has pre-existing anti-PEG antibodies in their circulation, possibly due to widespread exposure to PEG in commonly used products such as cosmetics, soaps, and medicines [10][11][12]16,[25][26][27][28][29][30][31].…”

“…Anti-PEG antibodies can bind and accelerate the clearance of pegylated enzymes, proteins, and nanocarriers conjugated with multiple PEG chains in animals ( Table 2) [18][19][20][21][22][23][32][33][34][35][36]. High levels of induced anti-PEG antibodies can also alter the half-life and biological activity of pegylated drugs in patients [7,8,11,14]. Pre-existing anti-PEG antibodies have also been linked to allergic reactions after the infusion of pegylated medicines [29,31].…”

How to solve the problem of hypersensitivity to asparaginase?

“…A Phase I study of this agent was successfully conducted in 10 adults aged 18–50 years (median, 40.6 years) without a previous history of allergic reaction to Erwinase; few if any of these patients would have been previously exposed to pegaspargase, a drug seldom used to treat adults with ALL, especially before native asparaginase was discontinued in the United States in December 2012. In this issue of Pediatric Blood & Cancer , Rau et al . from the Children's Oncology Group reported the results of a Phase II trial of intravenous pegcrisantaspase in pediatric patients with ALL or lymphoblastic lymphoma who had a history of grade 2 or more hypersensitivity reactions to pegaspargase.…”

“…As mentioned by Rau and colleagues, PEG has been used not only in the pharmaceutical industry but also in processed foods and cosmetics. Although PEG has been considered poorly immunogenic over the years, multiple recent studies have shown that anti‐PEG IgG and IgM can be detected at low levels in approximately 70% and at high levels in up to 7% of the general population, leading to serious reactions upon first exposure to PEGylated medicines .…”

“…Rau and associates proposed several strategies to circumvent the problems of pegaspargase hypersensitivity, such as the development of alternative “stealth” polymers and saturation of preexisting anti‐PEG antibodies with free, low molecular weight PEG prior to administration of subsequent pegaspargase. Whether cross‐reactivity of anti‐PEG antibodies to other polymers, alternative molecular weight PEG or modified PEG would hinder this strategy is unclear.…”