Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

Thommy Svahn; Karin Mellgren; Arja Harila-Saari; Ann Åsberg; Jukka Kanerva; Ólafur Jónsson; Goda Vaitkeviciene; Torben Stamm Mikkelssen; Kjeld Schmiegelow; Jesper Heldrup

doi:10.1002/pbc.26395

Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

Thommy Svahn, Karin Mellgren, Arja Harila-Saari, Ann Åsberg, Jukka Kanerva, Ólafur Jónsson, Goda Vaitkeviciene, Torben Stamm Mikkelssen, Kjeld Schmiegelow, Jesper Heldrup

Department of Clinical Medicine

15 Citations (Scopus)

Abstract

Background: Carboxypeptidase G2 (CPDG₂) 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/m²/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG₂ administration in cases of DME (clinicaltrials.gov NCT01305655). Results: Forty-seven of the 1,286 children (3.6%) received CPDG₂ during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG₂ was used during the first HDMtx course. Within a median of 6 hr from CPDG₂ 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 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: CPDG₂ 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.

Original language	English
Article number	e26395
Journal	Pediatric Blood & Cancer
Volume	64
Issue number	7
Number of pages	7
ISSN	1545-5009
DOIs	https://doi.org/10.1002/pbc.26395
Publication status	Published - Jul 2017

Keywords

Acute Kidney Injury/chemically induced
Adolescent
Antimetabolites, Antineoplastic/administration & dosage
Child
Child, Preschool
Female
Humans
Infant
Kidney/drug effects
Kidney Function Tests
Male
Methotrexate/administration & dosage
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
gamma-Glutamyl Hydrolase/therapeutic use

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10.1002/pbc.26395

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Svahn, T., Mellgren, K., Harila-Saari, A., Åsberg, A., Kanerva, J., Jónsson, Ó., Vaitkeviciene, G., Stamm Mikkelssen, T., Schmiegelow, K., & Heldrup, J. (2017). Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia. Pediatric Blood & Cancer, 64(7), [e26395]. https://doi.org/10.1002/pbc.26395

Svahn, T, Mellgren, K, Harila-Saari, A, Åsberg, A, Kanerva, J, Jónsson, Ó, Vaitkeviciene, G, Stamm Mikkelssen, T, Schmiegelow, K & Heldrup, J 2017, 'Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia', Pediatric Blood & Cancer, vol. 64, no. 7, e26395. https://doi.org/10.1002/pbc.26395

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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. 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/m2/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG2 administration in cases of DME (clinicaltrials.gov NCT01305655). Results: Forty-seven of the 1,286 children (3.6%) received CPDG2 during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG2 was used during the first HDMtx course. Within a median of 6 hr from CPDG2 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 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: CPDG2 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 = "Acute Kidney Injury/chemically induced, Adolescent, Antimetabolites, Antineoplastic/administration & dosage, Child, Child, Preschool, Female, Humans, Infant, Kidney/drug effects, Kidney Function Tests, Male, Methotrexate/administration & dosage, Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy, gamma-Glutamyl Hydrolase/therapeutic use",

author = "Thommy Svahn and Karin Mellgren and Arja Harila-Saari and Ann {\AA}sberg and Jukka Kanerva and {\'O}lafur J{\'o}nsson and Goda Vaitkeviciene and {Stamm Mikkelssen}, Torben and Kjeld Schmiegelow and Jesper Heldrup",

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year = "2017",

month = jul,

doi = "10.1002/pbc.26395",

language = "English",

volume = "64",

journal = "Pediatric Blood and Cancer",

issn = "1545-5009",

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TY - JOUR

T1 - Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

AU - Svahn, Thommy

AU - Mellgren, Karin

AU - Harila-Saari, Arja

AU - Åsberg, Ann

AU - Kanerva, Jukka

AU - Jónsson, Ólafur

AU - Vaitkeviciene, Goda

AU - Stamm Mikkelssen, Torben

AU - Schmiegelow, Kjeld

AU - Heldrup, Jesper

PY - 2017/7

Y1 - 2017/7

N2 - Background: Carboxypeptidase G2 (CPDG2) 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/m2/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG2 administration in cases of DME (clinicaltrials.gov NCT01305655). Results: Forty-seven of the 1,286 children (3.6%) received CPDG2 during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG2 was used during the first HDMtx course. Within a median of 6 hr from CPDG2 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 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: CPDG2 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.

AB - Background: Carboxypeptidase G2 (CPDG2) 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/m2/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG2 administration in cases of DME (clinicaltrials.gov NCT01305655). Results: Forty-seven of the 1,286 children (3.6%) received CPDG2 during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG2 was used during the first HDMtx course. Within a median of 6 hr from CPDG2 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 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: CPDG2 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.

KW - Acute Kidney Injury/chemically induced

KW - Adolescent

KW - Antimetabolites, Antineoplastic/administration & dosage

KW - Child

KW - Child, Preschool

KW - Female

KW - Humans

KW - Infant

KW - Kidney/drug effects

KW - Kidney Function Tests

KW - Male

KW - Methotrexate/administration & dosage

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

KW - gamma-Glutamyl Hydrolase/therapeutic use

U2 - 10.1002/pbc.26395

DO - 10.1002/pbc.26395

M3 - Journal article

C2 - 27966809

SN - 1545-5009

VL - 64

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

IS - 7

M1 - e26395

ER -

Delayed elimination of high-dose methotrexate and use of carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia

Abstract

Keywords

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