Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia

Natanja Oosterom; Robert de Jonge; Desiree E C Smith; Rob Pieters; Wim J E Tissing; Marta Fiocco; Bertrand D van Zelst; Marry M van den Heuvel-Eibrink; Sandra G Heil

doi:10.1371/journal.pone.0221591

Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia

Natanja Oosterom, Robert de Jonge, Desiree E C Smith, Rob Pieters, Wim J E Tissing, Marta Fiocco, Bertrand D van Zelst, Marry M van den Heuvel-Eibrink, Sandra G Heil

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

Abstract

BACKGROUND: Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could 'rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.

METHODS: We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.

RESULTS: Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9-11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9-74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.

CONCLUSION: Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

Original language	English
Article number	e0221591
Pages (from-to)	e0221591
Journal	PloS one
Volume	14
Issue number	9
DOIs	https://doi.org/10.1371/journal.pone.0221591
Publication status	Published - 2019

Keywords

Adolescent
Antidotes/administration & dosage
Child
Child, Preschool
Erythrocytes/drug effects
Female
Folic Acid/blood
Folic Acid Antagonists/administration & dosage
Homocysteine/blood
Humans
Infant
Leucovorin/administration & dosage
Male
Metabolic Networks and Pathways
Methotrexate/administration & dosage
Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood
Prospective Studies
Vitamin B 12/blood

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10.1371/journal.pone.0221591

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Oosterom, N., de Jonge, R., Smith, D. E. C., Pieters, R., Tissing, W. J. E., Fiocco, M., van Zelst, B. D., van den Heuvel-Eibrink, M. M., & Heil, S. G. (2019). Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia. PloS one, 14(9), e0221591. Article e0221591. https://doi.org/10.1371/journal.pone.0221591

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title = "Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia",

abstract = "BACKGROUND: Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could 'rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.METHODS: We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.RESULTS: Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9-11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9-74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.CONCLUSION: Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.",

keywords = "Adolescent, Antidotes/administration & dosage, Child, Child, Preschool, Erythrocytes/drug effects, Female, Folic Acid/blood, Folic Acid Antagonists/administration & dosage, Homocysteine/blood, Humans, Infant, Leucovorin/administration & dosage, Male, Metabolic Networks and Pathways, Methotrexate/administration & dosage, Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood, Prospective Studies, Vitamin B 12/blood",

author = "Natanja Oosterom and {de Jonge}, Robert and Smith, {Desiree E C} and Rob Pieters and Tissing, {Wim J E} and Marta Fiocco and {van Zelst}, {Bertrand D} and {van den Heuvel-Eibrink}, {Marry M} and Heil, {Sandra G}",

note = "Publisher Copyright: {\textcopyright} 2019 Oosterom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2019",

doi = "10.1371/journal.pone.0221591",

language = "English",

volume = "14",

pages = "e0221591",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "9",

}

Oosterom, N, de Jonge, R, Smith, DEC, Pieters, R , Tissing, WJE , Fiocco, M, van Zelst, BD, van den Heuvel-Eibrink, MM & Heil, SG 2019, 'Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia', PloS one, vol. 14, no. 9, e0221591, pp. e0221591. https://doi.org/10.1371/journal.pone.0221591

TY - JOUR

T1 - Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia

AU - Oosterom, Natanja

AU - de Jonge, Robert

AU - Smith, Desiree E C

AU - Pieters, Rob

AU - Tissing, Wim J E

AU - Fiocco, Marta

AU - van Zelst, Bertrand D

AU - van den Heuvel-Eibrink, Marry M

AU - Heil, Sandra G

N1 - Publisher Copyright: © 2019 Oosterom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2019

Y1 - 2019

N2 - BACKGROUND: Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could 'rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.METHODS: We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.RESULTS: Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9-11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9-74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.CONCLUSION: Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

AB - BACKGROUND: Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could 'rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.METHODS: We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.RESULTS: Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9-11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9-74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.CONCLUSION: Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

KW - Adolescent

KW - Antidotes/administration & dosage

KW - Child

KW - Child, Preschool

KW - Erythrocytes/drug effects

KW - Female

KW - Folic Acid/blood

KW - Folic Acid Antagonists/administration & dosage

KW - Homocysteine/blood

KW - Humans

KW - Infant

KW - Leucovorin/administration & dosage

KW - Male

KW - Metabolic Networks and Pathways

KW - Methotrexate/administration & dosage

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood

KW - Prospective Studies

KW - Vitamin B 12/blood

UR - http://www.scopus.com/inward/record.url?scp=85072297942&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0221591

DO - 10.1371/journal.pone.0221591

M3 - Article

C2 - 31527879

SN - 1932-6203

VL - 14

SP - e0221591

JO - PloS one

JF - PloS one

IS - 9

M1 - e0221591

ER -

Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia

Abstract

Keywords

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