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.

FIG 1.

Reactions by antibody status, preparation, and protocol. (A) Frequency of patients by their anti–Escherichia coli asparaginase (L-ASP) status and reaction to L-ASP in the Total XV study (TXV; upper chart). Distribution of patients who experienced reactions to L-ASP by their reaction grade (lower chart). (B) Frequency of patients by their anti-pegaspargase (PEG-ASP) status and reaction to PEG-ASP in Total XVI study (TXVI; upper chart). Distribution of patients who experienced reactions to PEG-ASP by their reaction grade (lower chart). All reactions are grade 2 or greater. Silent hypersensitivity (antibody positive but reaction negative) occurred in 89 (22%) of 410 and 107 (18%) of 598 patients on TXV versus TXVI (P = .13). Grade 2 to 4 reactions were less common (81 [13.5%] of 598 patients) in TXVI (to PEG-ASP) than in TXV (169 [41%] of 410 patients; to L-ASP; P = 1.4 × 10⁻²³), but a higher proportion were grade 3 or 4 (24 [14.2%] of 169 v 58 [71.6%] of 81; P = 1.5 × 10⁻¹⁹). Overall, there were more grade 3 or 4 reactions with PEG-ASP than L-ASP (P = .028). All P values were generated from χ² test. Reaction+, patients with allergic reactions to L-ASP (TXV) or PEG-ASP (TXVI); Reaction−, patients who received L-ASP (TXV) or PEG-ASP (TXVI) but did not have reactions to asparaginase.

FIG 2.

Association between anti-pegaspargase (PEG-ASP) antibody levels at different protocol time points and allergic reactions to PEG-ASP at any time during therapy in all Total XVI study (TXVI) patients (A; P values are .047, .098, 1.1E-4, 3.2E-13, 5.7E-24, 2.8E-25, 1.8E-25, 5.3E-21, and 3.9E-22 comparing reactive patients and nonreactive patients); TXVI low-risk arm (LR) patients (B; P values are .17, .14, 2.5E-4, 3.1E-7, 6.5E-12, 1.5E-10, 1.7E-11, 7.9E-13, and 5.0E-13 comparing reactive and nonreactive patients); and TXVI standard/high-risk arm (SHR) patients (C; P values are .19, .36, .066, 2.6E-7, 1.6E-13, 8.6E-16, 2.5E-15, 6.8E-10, and 1.6E-11 comparing reactive patients and nonreactive patients). cons, consolidation day 1; d1, induction day 1; d8, induction day 8; d15, induction day 15; OD, optical density; Reaction+, patients with allergic reactions at any time during therapy; Reaction−, patients who received PEG-ASP and never developed allergy; w7, continuation week 7; w8, continuation week 8; w9, continuation week 9; w17, continuation week 17; w19, continuation week 19.

FIG 3.

Association between anti-pegaspargase (PEG-ASP) status, reaction severity and clinical symptoms, and PEG-ASP rechallenge. (A) Association between the grade of the initial reaction and whether the patient was rechallenged or not (P = .0041). (B) Association between morbidity score assigned from clinical symptoms and rechallenge outcome (P = .0091). (C) Classification and regression tree of rechallenge outcome prediction.

FIG 4.

Sensitivity and specificity of antibodies for allergic reactions by risk arm. Sensitivity, specificity and area under the curve (AUC) of receiver operating characteristic (ROC) curves for the association between (A) anti-pegaspargase (PEG-ASP) antibody, (B) anti-PEG antibody, (C) and anti–Escherichia coli asparaginase (L-ASP) antibody measured at different protocol time points and allergic reactions to PEG-ASP at any time during therapy. cons, consolidation day 1; d1, induction day 1; d8, induction day 8; d15, induction day 15; LR, low-risk arm; SHR, standard/high-risk arm; w7, continuation week 7; w8, continuation week 8; w9, continuation week 9; w17, continuation week 17; w19, continuation week 19.

FIG 5.

Of samples that were positive for anti-pegaspargase, shown are the percent positive for anti-PEG and anti–Escherichia coli asparaginase (L-ASP) at each protocol time point in the Total XVI study. cons, consolidation day 1; d1, induction day 1; d8, induction day 8; d15, induction day 15; w7, continuation week 7; w8, continuation week 8; w9, continuation week 9; w17, continuation week 17; w19, continuation week 19.