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

Schmidt, Diana; Kristensen, Kim; Schroeder, Henrik; Wehner, Peder Skov; Rosthøj, Steen; Heldrup, Jesper LU ; Damsgaard, Linn; Schmiegelow, Kjeld and Mikkelsen, Torben Stamm (2019) In Pediatric Blood and Cancer 2019.
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... (More)


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.

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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
acute leukemias, ALL, chemotherapy, methotrexate, support care cancer pharmacology
in
Pediatric Blood and Cancer
volume
2019
publisher
John Wiley and Sons Inc.
external identifiers
  • scopus:85062522765
ISSN
1545-5009
DOI
10.1002/pbc.27637
language
English
LU publication?
no
id
9eedf70b-1731-4974-aa1f-99226ce9076e
date added to LUP
2019-03-19 08:46:49
date last changed
2019-04-10 04:21:21
@article{9eedf70b-1731-4974-aa1f-99226ce9076e,
  abstract     = {<p><br>
                                                         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                             <br>
                            <sup>2</sup><br>
                                                          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                             <br>
                            <sup>2</sup><br>
                                                          (n = 140 patients) or 8 g/m                             <br>
                            <sup>2</sup><br>
                                                          (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 &lt; 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.                         <br>
                        </p>},
  articleno    = {e27637},
  author       = {Schmidt, Diana and Kristensen, Kim and Schroeder, Henrik and Wehner, Peder Skov and Rosthøj, Steen and Heldrup, Jesper and Damsgaard, Linn and Schmiegelow, Kjeld and Mikkelsen, Torben Stamm},
  issn         = {1545-5009},
  keyword      = {acute leukemias,ALL,chemotherapy,methotrexate,support care cancer pharmacology},
  language     = {eng},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Pediatric Blood and Cancer},
  title        = {Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia : A Danish population-based study},
  url          = {http://dx.doi.org/10.1002/pbc.27637},
  volume       = {2019},
  year         = {2019},
}