Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

Jacob Nersting; Stine Nygaard Nielsen; Kathrine Grell; Maria Paerregaard; Jonas Abrahamsson; Bendik Lund; Olafur Gisli Jonsson; Kaie Pruunsild; Goda Vaitkeviciene; Jukka Kanerva; Kjeld Schmiegelow; Nordic Society of Paediatric Haematology and Oncology (NOPHO)

doi:10.1007/s00280-018-3704-7

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

Jacob Nersting, Stine Nygaard Nielsen, Kathrine Grell, Maria Paerregaard, Jonas Abrahamsson, Bendik Lund, Olafur Gisli Jonsson, Kaie Pruunsild, Goda Vaitkeviciene, Jukka Kanerva, Kjeld Schmiegelow, Nordic Society of Paediatric Haematology and Oncology (NOPHO)

4 Citations (Scopus)

Abstract

Purpose: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1–6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. Methods and results: Summed MTX with 1–6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58–7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2–27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2–50.2)% of MTXpg1–6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r _s = 0.68 and r _s = 0.25–0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all r _s ≥ 0.51. MTXpg4 accounted for 29.8 (24.7–33.3)% of MTXpg3–6, yet explained 96% of the summed MTXpg3–6 variation. MTXpg1–4, MTXpg1–6, MTXpg2–6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset. Conclusions: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

Original language	English
Journal	Cancer Chemotherapy and Pharmacology
Volume	83
Issue number	1
Pages (from-to)	53-60
Number of pages	8
ISSN	0344-5704
DOIs	https://doi.org/10.1007/s00280-018-3704-7
Publication status	Published - 31 Jan 2019

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Nersting, J., Nielsen, S. N., Grell, K., Paerregaard, M., Abrahamsson, J., Lund, B., Jonsson, O. G., Pruunsild, K., Vaitkeviciene, G., Kanerva, J., Schmiegelow, K., & Nordic Society of Paediatric Haematology and Oncology (NOPHO) (2019). Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy. Cancer Chemotherapy and Pharmacology, 83(1), 53-60. https://doi.org/10.1007/s00280-018-3704-7

Nersting, J, Nielsen, SN, Grell, K, Paerregaard, M, Abrahamsson, J, Lund, B, Jonsson, OG, Pruunsild, K, Vaitkeviciene, G, Kanerva, J, Schmiegelow, K & Nordic Society of Paediatric Haematology and Oncology (NOPHO) 2019, 'Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy', Cancer Chemotherapy and Pharmacology, vol. 83, no. 1, pp. 53-60. https://doi.org/10.1007/s00280-018-3704-7

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title = "Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy",

abstract = " Purpose: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1–6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. Methods and results: Summed MTX with 1–6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58–7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2–27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2–50.2)% of MTXpg1–6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r s = 0.68 and r s = 0.25–0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all r s ≥ 0.51. MTXpg4 accounted for 29.8 (24.7–33.3)% of MTXpg3–6, yet explained 96% of the summed MTXpg3–6 variation. MTXpg1–4, MTXpg1–6, MTXpg2–6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset. Conclusions: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified. ",

author = "Jacob Nersting and Nielsen, {Stine Nygaard} and Kathrine Grell and Maria Paerregaard and Jonas Abrahamsson and Bendik Lund and Jonsson, {Olafur Gisli} and Kaie Pruunsild and Goda Vaitkeviciene and Jukka Kanerva and Kjeld Schmiegelow and {Nordic Society of Paediatric Haematology and Oncology (NOPHO)}",

year = "2019",

month = jan,

day = "31",

doi = "10.1007/s00280-018-3704-7",

language = "English",

volume = "83",

pages = "53--60",

journal = "Cancer Chemotherapy and Pharmacology, Supplement",

issn = "0943-9404",

publisher = "Springer",

number = "1",

}

TY - JOUR

T1 - Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

AU - Nersting, Jacob

AU - Nielsen, Stine Nygaard

AU - Grell, Kathrine

AU - Paerregaard, Maria

AU - Abrahamsson, Jonas

AU - Lund, Bendik

AU - Jonsson, Olafur Gisli

AU - Pruunsild, Kaie

AU - Vaitkeviciene, Goda

AU - Kanerva, Jukka

AU - Schmiegelow, Kjeld

AU - Nordic Society of Paediatric Haematology and Oncology (NOPHO)

PY - 2019/1/31

Y1 - 2019/1/31

N2 - Purpose: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1–6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. Methods and results: Summed MTX with 1–6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58–7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2–27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2–50.2)% of MTXpg1–6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r s = 0.68 and r s = 0.25–0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all r s ≥ 0.51. MTXpg4 accounted for 29.8 (24.7–33.3)% of MTXpg3–6, yet explained 96% of the summed MTXpg3–6 variation. MTXpg1–4, MTXpg1–6, MTXpg2–6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset. Conclusions: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

AB - Purpose: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1–6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. Methods and results: Summed MTX with 1–6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58–7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2–27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2–50.2)% of MTXpg1–6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r s = 0.68 and r s = 0.25–0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all r s ≥ 0.51. MTXpg4 accounted for 29.8 (24.7–33.3)% of MTXpg3–6, yet explained 96% of the summed MTXpg3–6 variation. MTXpg1–4, MTXpg1–6, MTXpg2–6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset. Conclusions: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

U2 - 10.1007/s00280-018-3704-7

DO - 10.1007/s00280-018-3704-7

M3 - Journal article

C2 - 30324220

SN - 0943-9404

VL - 83

SP - 53

EP - 60

JO - Cancer Chemotherapy and Pharmacology, Supplement

JF - Cancer Chemotherapy and Pharmacology, Supplement

IS - 1

ER -

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

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