Received: 30 July 2016 Revised: 3 October 2016 Accepted: 10 November 2016 DOI: 10.1002/pbc.26395 Pediatric Blood & Cancer The American Society of Pediatric Hematology/Oncology RESEARCH ARTICLE Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia Thommy Svahn 1 Karin Mellgren 1 Arja Harila-Saari 2 Ann ˚ Asberg 3 Jukka Kanerva 4 Ólafur Jónsson 5 Goda Vaitkeviciene 6 Torben Stamm Mikkelssen 7 Kjeld Schmiegelow 8 Jesper Heldrup 9 1 Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothen- burg, Sweden 2 Department of Women’s and Children’s Health, Karolinska Institutet and Astrid Lindgren Chil- dren’s Hospital, Karolinska Hospital, Stockholm, Sweden 3 Pediatric Department, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway 4 Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland 5 Children’s Hospital, Landspítali University Hospital, Reykjavik, Iceland 6 Children’s Hospital, Affiliate of Vilnius Univer- sity Hospital Santariskiu Klinikos and Vilnius University, Vilnius, Lithuania 7 Department of Pediatrics, Aarhus University, Denmark 8 Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Den- mark 9 Department of Pediatrics, Skåne University Hospital, Lund, Sweden Correspondence Karin Mellgren, Pediatric Oncology and Hema- tology, The Queen Silvia’s Hospital for Children and Adolescents, Rondvägen 10, 41685 Gothen- burg, Sweden. Email: karin.mellgren@vgregion.se Abstract Background: Carboxypeptidase G2 (CPDG 2 ) can be used as rescue treatment in cases of delayed methotrexate elimination (DME) and Mtx-induced nephrotoxicity. Procedure: 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/m 2 /24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG 2 administration in cases of DME (clinicaltrials.gov NCT01305655). Results: Forty-seven of the 1,286 children (3.6%) received CPDG 2 during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG 2 was used during the first HDMtx course. Within a median of 6 hr from CPDG 2 administration, 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 lev- els ≤ 0.2 M 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 < 1m 2 (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: CPDG 2 administration is highly effective as rescue in case of delayed Mtx clearance. Subsequent HDMtx courses could be administered without events in most of the patients. KEYWORDS ALL, children, delayed methotrexate elimination, glucarpidase 1 INTRODUCTION In the Nordic and Baltic countries (Nordic Organization for Pediatric Hematology and Oncology, NOPHO), approximately 200 pediatric Abbreviations: ALL, acute lymphoblastic leukemia; BSA, body surface area; CPDG 2 , carboxypeptidase G2; cMtx, concentration of methotrexate; DAMPA, 2,4-diamino-N 10 -methylpteroic acid; DME, delayed methotrexate elimination; EMIT, enzyme-multiplied immunoassay technique; FPIA 1–2, fluorescence polarization immunoassay 1 or 2; HDMtx, high-dose methotrexate; HPLC, High-performance liquid chromatography; Mtx, methotrexate; NOPHO, Nordic Organization for Pediatric Hematology and Oncology patients per year are diagnosed with acute lymphoblastic leukemia (ALL). 1 High-dose methotrexate (HDMtx), typically defined as doses > 1 g/m 2 , 2 administered as a continuous intravenous (i.v.) infusion, 3 has been an important mainstay of the NOPHO ALL protocols since 1981. Despite supportive care, HDMtx can induce nephrotoxicity with delayed Mtx elimination (DME) and prolonged high plasma Mtx concentrations. 4 HDMtx-induced nephrotoxicity is hypothesized to be mediated via direct tubular toxicity 5 or by pH- dependent precipitation of Mtx and its metabolites in renal tubules. 6 HDMtx-induced renal damage reduces Mtx clearance and increases Pediatr Blood Cancer 2016; 00: 1–7 c  2016 Wiley Periodicals, Inc. 1 wileyonlinelibrary.com/journal/pbc