title: Statistical analysis of relation between plasma methotrexate concentration and toxicity in high-dose methotrexate therapy of childhood nonHodgkin lymphoma.
abstract: Plasma monitoring of Methotrexate (MTX) levels is a standard approach to predict MTX-related toxicities in a high-dose (HD) MTX monotherapy for childhood acute lymphoblastic leukemia. However, it is uncertain whether plasma MTX levels can predict MTX-related toxicity in the HDMTX plus additional chemotherapy for childhood B-cell nonHodgkin lymphoma (B-NHL).
  
  
  
  To statistically analyze the relationship between MTX pharmacokinetic parameters and MTX-related toxicities, we collected data from patients with delayed MTX elimination (≥1 µM at 48 hr and/or ≥0.5 µM at 72 hr) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) BNHL 03 study. Blood MTX levels were measured at 24, 48, and 72 hr after 3 or 5 g/m2HD-MTX administration for 24 hr.
  
  
  
  Three hundred and four patients received 2-4 courses of the HDMTX plus additional chemotherapy, and delayed MTX elimination was observed in 165 courses of 127 patients. In those, nephrotoxicity was significantly correlated with plasma MTX levels for each patient (P = 0.03), and also for each course (P = 0.009), but no other toxicities were correlated. Another analysis according to HDMTX courses showed no significant correlation between the first high plasma MTX levels and subsequent MTX levels in later course. It also showed that incidence of liver and gastrointestinal toxicities was most frequent in the first HDMTX course, and then sharply decreased in later courses (P < 0.001).
  
  
  
  Our results suggest that plasma MTX level is not a reliable predictor for adverse events except for nephrotoxicity in multiple HDMTX therapy courses in childhood B-NHL. Pediatr Blood Cancer 2015;62:279-284. © 2014 Wiley Periodicals, Inc.
authors.affiliation: The Advanced Medical Research Center, Aichi Medical University, Aichi, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Tsurusawa
authors.affiliation: The Advanced Medical Research Center, Aichi Medical University, Aichi, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Gosho
authors.affiliation: Division of Pediatric Oncology, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Pediatrics, Yamagata University Hospital, Yamagata, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Mitsui
authors.affiliation: Department of Pediatrics, Japanese Red Cross Narita Hospital, Chiba, Japan.
authors.forename: Shosuke
authors.initials: S
authors.lastname: Sunami
authors.affiliation: Department of Pediatrics, Sapporo Hokuyu Hospital, Sapporo, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Kushu Cancer Center, Fukuoka, Japan.
authors.forename: Reiji
authors.initials: R
authors.lastname: Fukano
authors.affiliation: Department of Pediatrics, Saiseikai Yokohama Nanbu Hospital, Kanagawa, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Department of Pediatrics, Kurume University Hospital, Kurume, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Inada
authors.affiliation: Department of Hematology-Oncology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takimoto
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito
authors.affiliation: Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: Department of Pathology, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakazawa
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Horibe
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced*; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis*; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate
keywords: HDMTX; childhood; nonHodgkin lymphoma; toxicity