title: Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia.
abstract: BACKGROUND
  Carboxypeptidase G2 (CPDG2) can be used as rescue treatment in cases of delayed methotrexate elimination (DME) and Mtx-induced nephrotoxicity.
  
  
  METHODS
  Between July 2008 and December 2014, all children (1.0-17.9 years) in the Nordic countries diagnosed with Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) were treated according to the Nordic Organization for Pediatric Hematology and Oncology (NOPHO) ALL 2008 protocol, including administration of six to eight high-dose (5 g/m2/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG2administration in cases of DME (clinicaltrials.gov NCT01305655).
  
  
  RESULTS
  Forty-seven of the 1,286 children (3.6%) received CPDG2during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG2was used during the first HDMtx course. Within a median of 6 hr from CPDG2administration, the Mtx concentration decreased by 75% when measured with immune-based methods, and by 100% when measured with high-performance liquid chromatography. The median time from the start of Mtx infusion to plasma levels ≤ 0.2 μM was 228 hr (range: 48-438). The maximum increase in plasma creatinine was 375% (range: 100-1,310). Creatinine peaked after a median of 48 hr (range: 36-86). Mtx elimination time was shorter in patients with body surface area < 1 m2(median 198.5 vs. 257 hr; P = 0.004) and was inversely correlated to the maximum creatinine increase (209 vs. 258 hr; P = 0.034). All patients normalized their renal function as measured with s-creatinine.
  
  
  CONCLUSIONS
  CPDG2administration is highly effective as rescue in case of delayed Mtx clearance. Subsequent HDMtx courses could be administered without events in most of the patients.
authors.affiliation: Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Thommy
authors.initials: T
authors.lastname: Svahn
authors.affiliation: Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Mellgren
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet and Astrid Lindgren Children's Hospital, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Arja
authors.initials: A
authors.lastname: Harila-Saari
authors.affiliation: Pediatric Department, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
authors.forename: Ann
authors.initials: A
authors.lastname: Åsberg
authors.affiliation: Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Kanerva
authors.affiliation: Children's Hospital, Landspítali University Hospital, Reykjavik, Iceland.
authors.forename: Ólafur
authors.initials: Ó
authors.lastname: Jónsson
authors.affiliation: Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos and Vilnius University, Vilnius, Lithuania.
authors.forename: Goda
authors.initials: G
authors.lastname: Vaitkeviciene
authors.affiliation: Department of Pediatrics, Aarhus University, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Stamm Mikkelssen
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Schmiegelow
authors.affiliation: Department of Pediatrics, Skåne University Hospital, Lund, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Heldrup
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control*; D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate
keywords: ALL; children; delayed methotrexate elimination; glucarpidase