Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia

Abstract

Asparaginase is an effective antileukemic agent and is included in most front-line protocols for pediatric acute lymphoblastic leukemia (ALL) worldwide; however, allergic reactions to asparaginase may be dose-limiting. We evaluated plasma anti-asparaginase antibody concentrations in a cohort of children with newly diagnosed ALL, who did and who did not exhibit clinical hypersensitivity, after Escherichia coli (E. coli) asparaginase therapy. Thirty-five children who received asparaginase 10 000 IU/m 2 i.m. three times weekly for nine doses as part of both multiagent induction and reinduction chemotherapy, and seven monthly doses during the first 7 months of continuation treatment, were studied. Twenty-two patients experienced initial allergic reactions to asparaginase during continuation (n = 20) or reinduction (n = 2) phases and 13 children did not exhibit any reaction. An enzyme-linked immunosorbent assay (ELISA) was used to measure anti-asparaginase antibodies in plasma samples, diluted 1:3200, using E. coli asparaginase as the antigen. The median anti-asparaginase antibody concentration (OD at 1:3200 dilution) increased from 0.039 at induction to 0.506 at reinduction in patients who exhibited clinical hypersensitivity (P = 0.0002). By comparison, median antibody level increased from 0.011 to 0.032 OD at identical time points in patients who did not react to asparaginase (P = 0.02). Both post-induction and post-reinduction anti-asparaginase antibody levels were higher in reacting than in nonreacting patients (P = 0.004 and P = 0.01, respectively). Antibody levels were inversely related to the time elapsed between the reaction and sampling (P = 0.011). Although anti-asparaginase antibody levels increased from the post-induction plasma sample to the post-reinduction sample in 28 of 35 patients regardless of whether they exhibited clinical hypersensitivity, patients with hypersensitivity reactions had higher antibody levels than did identically treated control patients at comparable time points in therapy. Therefore, antibody analysis may be of clinical value in predicting future hypersensitivity.

Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients

“…12 Asparaginase-specific IgG antibodies appear to correlate with clinical allergic reactions. 13,14 The severity of hypersensitivity reactions to the three asparaginase preparations ranges from mild allergic reactions to anaphylactic shock. 7,[14][15][16][17][18][19][20] The reported frequency of antiasparaginase antibodies was as high as 78% in adults and 70% in children following intravenous or intramuscular administration of E. coli asparaginase.…”

“…13,14 The severity of hypersensitivity reactions to the three asparaginase preparations ranges from mild allergic reactions to anaphylactic shock. 7,[14][15][16][17][18][19][20] The reported frequency of antiasparaginase antibodies was as high as 78% in adults and 70% in children following intravenous or intramuscular administration of E. coli asparaginase. 21 In all, 23-30% of children developed allergic reaction while receiving Erwinia asparaginase.…”

“…21 In all, 23-30% of children developed allergic reaction while receiving Erwinia asparaginase. 14,17 Allergic reaction was observed in 30-41% of patients who received PEG asparaginase. 18,22 Recently, the importance of 'silent hypersensitivity' has been recognized in patients who developed antiasparaginase antibodies without clinical evidence of a hypersensitivity reaction.…”

“…Hypersensitivity reactions usually require discontinuation of E. coli asparaginase and substitution with the Erwinia preparation. 6,7,14 The properties of PEG asparaginase were intended to reduce the immunogenicity and the risk of hypersensitivity reactions and to prolong the half-life of the drug. 24 Thus, PEG asparaginase has been used in patients who have prior allergy to E. coli or Erwinia asparaginase.…”

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

“…Anti-asparaginase antibodies occur in as many as 70% of children receiving E. coli asparaginase. 3,[10][11][12] The best course of action, including the use of premedications and substitution with PEG, or Erwinia asparaginase, in cases with frank or silent hypersensitivity to E. coli asparaginase, is also not clear.…”