Hypersensitive reactions and antibody formation during L-asparaginase treatment of children and adults with acute leukemia

Killander, D.; Dohlwitz, A.; Engstedt, L.; Franzén, S.; Gahrton, Gösta; Gullbring, B; Holm, Göran; Holmgren, Arne; Höglund, S; Killander, A.; Lockner, D.; Mellstedt, Håkan; Pj, Moe; Palmblad, Jan; Reizenstein, Peter; Skårberg, Karl Olof; Swedberg, B; Udén, Ann-Mari; Wadman, B.; Wide, Leif; Åhström, L.

doi:10.1002/1097-0142(197601)37:1<220::aid-cncr2820370132>3.0.co;2-w

Cited by 130 publications

(83 citation statements)

References 13 publications

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“…Antiasparaginase antibodies have been associated with increased drug clearance thus shortening its half-life, 8,9 decreasing circulating enzyme activity, 10,11 or lowering enzyme activity by deposition of antigen-antibody complex in the reticuloendothelial system. 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.…”

Section: Introductionmentioning

confidence: 99%

“…18,22 Recently, the importance of 'silent hypersensitivity' has been recognized in patients who developed antiasparaginase antibodies without clinical evidence of a hypersensitivity reaction. 6,9,12,21 Investigators found that those patients had a significant reduction in plasma asparaginase activity 9 and suboptimal asparagine depletion. 23 Allergic reactions to one preparation can be circumvented in most patients by the substitution to another preparation.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2003

Leukemia

109

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To evaluate how well antibodies to one asparaginase preparation predict or correlate with antibodies to another preparation in acute lymphoblastic leukemia (ALL) and lymphoma patients who did and did not have hypersensitivity reactions during chemotherapy. In all, 24 children with newly diagnosed ALL or lymphoma, who received Escherichia coli asparaginase 10 000 IU/ m 2 IM thrice weekly for nine doses as part of multiagent induction and reinduction chemotherapy, and seven monthly doses during the first 7 months of continuation treatment, were studied. Plasma samples were collected at postinduction and at postreinduction. Six of 24 patients had no overt clinical reactions (nonreacting) and received only the E. coli preparation. Of these, 18 patients who had allergic reactions were switched to Erwinia asparaginase. A total of 18 patients had an anaphylactoid reaction to Erwinia asparaginase and were switched to receive polyethylene glycol (PEG) asparaginase. Antibody levels were measured by enzyme-linked immunoadsorbent assay against all the three asparaginase preparations. At postinduction, antibodies against E. coli were higher in reacting patients (0.06370.066) than in nonreacting patients (0.01970.013) (P ¼ 0.03). At postreinduction, anti-Erwinia antibodies were significantly higher in reacting patients (0.43170.727) than in nonreacting patients (0.01870.009) (P ¼ 0.007). Anti-E. coli antibodies correlated with anti-PEG antibodies at postinduction (r ¼ 0.714, Po0.001) and at postreinduction (r ¼ 0.914, Po0.001), but did not correlate with anti-Erwinia antibodies at postinduction (r ¼ 0.119, P ¼ 0.580) and at postreinduction (r ¼ 0.078, P ¼ 0.716). The results indicate a crossreactivity between patient antibodies raised against natural E. coli and PEG asparaginase but not Erwinia asparaginase.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2003

Leukemia

109

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

et al. 2004

Leukemia

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Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (7s.d.) CSF asparagine (0.2970.63, n ¼ 9) than those who received PEG (0.7770.82, n ¼ 4) (P ¼ 0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.

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“…9 It has been suggested that development of antibodies may hamper the antileukemic effect of asparaginase by shortening its half-life, preventing or delaying absorption after intramuscular injection, or interfering with enzyme activity. 3,10,11 The reported frequency of anti-asparaginase antibodies is quite variable, and so high in some subgroups of patients (ie over 70% in adults receiving E. coli asparaginase) 10,12 that it is not clear whether antibody levels are more frequently detected or higher in patients who exhibit overt clinical allergy than in identically treated patients without clinical evidence of hypersensitivity. Therefore, the objective of this study was to retrospectively compare anti-asparaginase antibody concentrations at identical time points relative to therapy in ALL patients who did and who did not develop hypersensitivity reactions to asparaginase.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1998

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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.

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Hypersensitive reactions and antibody formation during L-asparaginase treatment of children and adults with acute leukemia

Cited by 130 publications

References 13 publications

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

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

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

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

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