Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge
Menée à partir d'échantillons sériques prélevés sur 598 patients atteints d'une leucémie lymphoblastique aiguë traitée par pégaspargase et sur 5 369 patients traités par L-asparaginase, cette étude identifie les facteurs associés au risque de réaction allergique liée à la pégaspargase et met en évidence l'intérêt de doser les anticorps anti-pégaspargase pour diagnostiquer une réaction allergique ou identifier les patients susceptibles de présenter une réaction allergique lors d'une seconde administration du médicament
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.
Journal of Clinical Oncology , résumé, 2018