Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge

Abstract

PURPOSE Pegaspargase (PEG-ASP) has largely replaced native Escherichia coli asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome. PATIENTS AND METHODS PEG-ASP was administered to 598 patients in St Jude’s Total XVI study. Results were compared with Total XV study ( ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111 ), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti–PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti–polyethylene glycol (PEG) and anti–L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics. RESULTS Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; P = 1.4 × 10−23). For Total XVI, anti-PEG, not anti–L-ASP, was the predominant component of anti–PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions ( P = 2.4 × 10−5), which is consistent with an immunosuppressant contribution of IT. Anti–PEG-ASP was associated with accelerated drug clearance ( P = 5.0 × 10−6). Failure of rechallenge after initial reactions was associated with anti–PEG-ASP ( P = .0078) and was predicted by the occurrence of angioedema with first reaction ( P = .01). CONCLUSION Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti–PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

“…Solid red arrows indicate dexamethasone treatment time periods; open orange arrows indicate asparaginase treatment time periods. Details of therapy have been described . Grade 4 hypertriglyceridemia (1000 mg/dL) is indicated with a dashed horizontal line.…”

“…S3). Anti‐asparaginase antibodies against l ‐asparaginase (TXV) and PEG‐asparaginase (TXVI) were measured as reported; patients were classified as positive or negative for antibodies at or prior to week 7 of continuation.…”

“…6,17 Our aim was to compare triglycerides, risk factors for hypertriglyceridemia, and associated toxicities in two front-line pediatric ALL trials that used identical glucocorticoid regimens but different formulations of asparaginase: Total XV study (native L-asparaginase) and Total XVI study (PEG-asparaginase). [21][22][23] with SHR patients receiving more intensive treatment.…”

Desensitization to pegaspargase in children with acute lymphoblastic leukemia and lymphoblastic lymphoma

“…When ERW is not available, the only options for patients who experience a hypersensitivity reaction are discontinuation of all asparaginase therapy or to rechallenge with pegaspargase. Rechallenging patients with pegaspargase is not routinely practiced, and leads to high rates of subsequent reactions in 40% to 83% of patients …”

“…Rechallenging patients with pegaspargase is not routinely practiced, and leads to high rates of subsequent reactions in 40% to 83% of patients. 18,19 Rapid desensitization is an effective method for rechallenging patients who have had a hypersensitivity reaction to chemotherapy agents. 14,15 Rapid desensitization induces temporary unresponsiveness to drug antigens, allowing patients to receive treatment with a medication to which they have had a prior immune-mediated reaction.…”