Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study

Diana Schmidt; Kim Kristensen; Henrik Schrøder; Peder Skov Wehner; Steen Rosthøj; Jesper Heldrup; Linn Damsgaard; Kjeld Schmiegelow; Torben Stamm Mikkelsen

doi:10.1002/pbc.27637

Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study

Diana Schmidt, Kim Kristensen, Henrik Schrøder, Peder Skov Wehner, Steen Rosthøj, Jesper Heldrup, Linn Damsgaard, Kjeld Schmiegelow, Torben Stamm Mikkelsen

Department of Clinical Medicine

3 Citations (Scopus)

Abstract

Background: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. Methods: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m ² on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0–9.9 μM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 μM. Results: Median 42-hour plasma MTX was 0.61 μM (interquartile range, 0.4–1.06 μM). Of 1295 MTX infusions with 5 g/m ² (n = 140 patients) or 8 g/m ² (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 μM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%–97%) and a specificity of 85% (95% CI, 83%–87%) for predicting 42-hour MTX ≥4.0 μM. Conclusions: A 25 μM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.

Original language	English
Article number	e27637
Journal	Pediatric Blood & Cancer
Volume	66
Issue number	6
Number of pages	6
ISSN	1545-5009
DOIs	https://doi.org/10.1002/pbc.27637
Publication status	Published - Jun 2019

Keywords

Faculty of Science
Acute leukemias
ALL
Chemotherapy
Methotrexate
Support care cancer pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pbc.27637

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Schmidt, D., Kristensen, K., Schrøder, H., Wehner, P. S., Rosthøj, S., Heldrup, J., Damsgaard, L., Schmiegelow, K., & Mikkelsen, T. S. (2019). Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study. Pediatric Blood & Cancer, 66(6), [e27637]. https://doi.org/10.1002/pbc.27637

Schmidt, D, Kristensen, K, Schrøder, H, Wehner, PS, Rosthøj, S, Heldrup, J, Damsgaard, L, Schmiegelow, K & Mikkelsen, TS 2019, 'Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study', Pediatric Blood & Cancer, vol. 66, no. 6, e27637. https://doi.org/10.1002/pbc.27637

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title = "Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study",

abstract = " Background: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. Methods: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m 2 on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0–9.9 μM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 μM. Results: Median 42-hour plasma MTX was 0.61 μM (interquartile range, 0.4–1.06 μM). Of 1295 MTX infusions with 5 g/m 2 (n = 140 patients) or 8 g/m 2 (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 μM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%–97%) and a specificity of 85% (95% CI, 83%–87%) for predicting 42-hour MTX ≥4.0 μM. Conclusions: A 25 μM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX. ",

keywords = "Faculty of Science, Acute leukemias, ALL, Chemotherapy, Methotrexate, Support care cancer pharmacology",

author = "Diana Schmidt and Kim Kristensen and Henrik Schr{\o}der and Wehner, {Peder Skov} and Steen Rosth{\o}j and Jesper Heldrup and Linn Damsgaard and Kjeld Schmiegelow and Mikkelsen, {Torben Stamm}",

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year = "2019",

month = jun,

doi = "10.1002/pbc.27637",

language = "English",

volume = "66",

journal = "Pediatric Blood and Cancer",

issn = "1545-5009",

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TY - JOUR

T1 - Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia

T2 - A Danish population-based study

AU - Schmidt, Diana

AU - Kristensen, Kim

AU - Schrøder, Henrik

AU - Wehner, Peder Skov

AU - Rosthøj, Steen

AU - Heldrup, Jesper

AU - Damsgaard, Linn

AU - Schmiegelow, Kjeld

AU - Mikkelsen, Torben Stamm

PY - 2019/6

Y1 - 2019/6

N2 - Background: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. Methods: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m 2 on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0–9.9 μM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 μM. Results: Median 42-hour plasma MTX was 0.61 μM (interquartile range, 0.4–1.06 μM). Of 1295 MTX infusions with 5 g/m 2 (n = 140 patients) or 8 g/m 2 (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 μM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%–97%) and a specificity of 85% (95% CI, 83%–87%) for predicting 42-hour MTX ≥4.0 μM. Conclusions: A 25 μM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.

AB - Background: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. Methods: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m 2 on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0–9.9 μM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 μM. Results: Median 42-hour plasma MTX was 0.61 μM (interquartile range, 0.4–1.06 μM). Of 1295 MTX infusions with 5 g/m 2 (n = 140 patients) or 8 g/m 2 (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 μM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%–97%) and a specificity of 85% (95% CI, 83%–87%) for predicting 42-hour MTX ≥4.0 μM. Conclusions: A 25 μM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.

KW - Faculty of Science

KW - Acute leukemias

KW - ALL

KW - Chemotherapy

KW - Methotrexate

KW - Support care cancer pharmacology

U2 - 10.1002/pbc.27637

DO - 10.1002/pbc.27637

M3 - Journal article

C2 - 30835935

SN - 1545-5009

VL - 66

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

IS - 6

M1 - e27637

ER -

Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study

Abstract

Keywords

UN SDGs

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