title: Plasma asparaginase activity, asparagine concentration, and toxicity after administration of Erwinia asparaginase in children and young adults with acute lymphoblastic leukemia: Phase I/II clinical trial in Japan.
abstract: BACKGROUND
  A phase I/II study of Erwinia asparaginase in Japanese children and young adults with acute lymphoblastic leukemia (ALL) was performed to investigate its activity and toxicity.
  
  
  METHODS
  Eligible patients were in remission and had developed allergy to Escherichia coli asparaginase. Erwina asparaginase was intramuscularly administrated on days 2, 5, 7, 9, 11, and 13. To measure the plasma l-asparagine concentration (PAC), amino acids were derivatized with Nα-(5-fluoro-2,4-dinitrophenyl)-l-leucinamide.
  
  
  RESULTS
  Six consecutive patients completed the phase I study with 25,000 IU/m2per dose without dose-limiting toxicity and 18 patients completed the phase II study with 25,000 IU/m2per dose. Median age of 24 patients was 7.5 (range 2-16) years. The half-life of plasma asparaginase activity (PAA) was 16.9 ± 7.5 hr and the maximum PAA was 3.10 ± 1.47 IU/ml (n = 23, noncompartment model). PAA of 0.1 IU/ml or more was achieved in all 23 patients (100%) 48 hr and in 18 of 23 patients (78.3%) 72 hr after the first administration. During the 2-week study, 94.2% (65 of 69) of the 48-hr samples and 80.4% (37 of 46) of the 72-hr samples had PAA of 0.1 IU/ml or more. PAC less than 1.0 μM was achieved in 95.7% patients 48 and 72 hr after administration. PAC values in all the samples were greater than the limit of quantitation (0.0625 μM). Karnofsky performance status of all patients was good during the 2-week study.
  
  
  CONCLUSIONS
  Erwinia asparaginase 25,000 IU/m2per dose × six intramuscular administrations in 2 weeks was well tolerated, pharmacologically efficacious, and safe in Japanese patients with ALL/lymphoblastic lymphoma.
authors.affiliation: Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Ogawa
authors.affiliation: Research and Development Division, OHARA Pharmaceutical Co., Ltd., Shiga, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Taguchi
authors.affiliation: Division of Hemato-Oncology and Regenerative Medicine, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomizawa
authors.affiliation: Department of Pediatrics, Toho University, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohara
authors.affiliation: Division of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001215:Asparaginase / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001216:Asparagine / Q000097:blood; D001426:Bacterial Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004885:Erwinia / Q000201:enzymology; D005260:Female; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D007564:Japan; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D001216:Asparagine; D001215:Asparaginase
keywords: acute lymphoblastic leukemia; asparaginase; childhood ALL, Erwinia asparaginase