title: Asparaginase antibody and asparaginase activity in children with higher-risk acute lymphoblastic leukemia: Children's Cancer Group Study CCG-1961.
abstract: We investigated the anti-asparaginase antibody (Ab) and asparaginase enzymatic activity in the sera of 1,001 patients (CCG-1961) with high-risk acute lymphoblastic leukemia (HR-ALL). Patients received nine doses of native Escherichia coli asparaginase during induction. Half of rapid early responders (RER) were randomly assigned to standard intensity arms and continued to receive native asparaginase. The other RER patients and all slow early responders received 6 or 10 doses of PEG-asparaginase. Serum samples (n = 3,193) were assayed for determination of asparaginase Ab titers and enzymatic activity. Three hundred ninety of 1,001 patients (39%) had no elevation of Ab among multiple evaluations-that is, were Ab-negative (<1.1 over negative control)-and 611 patients (61%) had an elevated Ab titer (>1.1). Among these 611 patients, 447 had no measurable asparaginase activity during therapy. Patients who were Ab-positive but had no clinical allergies continued to receive E. coli asparaginase, the activity of which declined precipitately. No detectable asparaginase activity was found in 81 of 88 Ab-positive patients shortly after asparaginase injections (94% neutralizing Ab). The Ab-positive patients with clinical allergies subsequently were given Erwinase and achieved substantial activity (0.1-0.4 IU/ml). An interim analysis of 280 patients who were followed for 30 months from induction demonstrated that the Ab-positive titers during interim maintenance-1 and in delayed intensification-1 were associated with an increased rate of events. The CCG-1961 treatment schedule was very immunogenic, plausibly due to initially administrated native asparaginase. Anti-asparaginase Ab was associated with undetectable asparaginase activity and may be correlated with adverse outcomes in HR ALL.
authors.affiliation: Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Eduard H
authors.initials: EH
authors.lastname: Panosyan
authors.forename: Nita L
authors.initials: NL
authors.lastname: Seibel
authors.forename: Sagrario
authors.initials: S
authors.lastname: Martin-Aragon
authors.forename: Paul S
authors.initials: PS
authors.lastname: Gaynon
authors.forename: Ioannis A
authors.initials: IA
authors.lastname: Avramis
authors.forename: Harland
authors.initials: H
authors.lastname: Sather
authors.forename: Janet
authors.initials: J
authors.lastname: Franklin
authors.forename: James
authors.initials: J
authors.lastname: Nachman
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Ettinger
authors.forename: Mei
authors.initials: M
authors.lastname: La
authors.forename: Peter
authors.initials: P
authors.lastname: Steinherz
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Cohen
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Siegel
authors.forename: Vassilios I
authors.initials: VI
authors.lastname: Avramis
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000097:blood* / Q000276:immunology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001215:Asparaginase / Q000097:blood* / Q000276:immunology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007958:Leukocyte Count; D008297:Male; D009500:Neutralization Tests; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001215:Asparaginase