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

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 an...

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Autores principales: Oosterom, Natanja, de Jonge, Robert, Smith, Desiree E. C., Pieters, Rob, Tissing, Wim J. E., Fiocco, Marta, van Zelst, Bertrand D., van den Heuvel-Eibrink, Marry M., Heil, Sandra G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748431/
https://www.ncbi.nlm.nih.gov/pubmed/31527879
http://dx.doi.org/10.1371/journal.pone.0221591
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author Oosterom, Natanja
de Jonge, Robert
Smith, Desiree E. C.
Pieters, Rob
Tissing, Wim J. E.
Fiocco, Marta
van Zelst, Bertrand D.
van den Heuvel-Eibrink, Marry M.
Heil, Sandra G.
author_facet Oosterom, Natanja
de Jonge, Robert
Smith, Desiree E. C.
Pieters, Rob
Tissing, Wim J. E.
Fiocco, Marta
van Zelst, Bertrand D.
van den Heuvel-Eibrink, Marry M.
Heil, Sandra G.
author_sort Oosterom, Natanja
collection PubMed
description 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.
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spelling pubmed-67484312019-09-27 Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia Oosterom, Natanja de Jonge, Robert Smith, Desiree E. C. Pieters, Rob Tissing, Wim J. E. Fiocco, Marta van Zelst, Bertrand D. van den Heuvel-Eibrink, Marry M. Heil, Sandra G. PLoS One Research Article 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. Public Library of Science 2019-09-17 /pmc/articles/PMC6748431/ /pubmed/31527879 http://dx.doi.org/10.1371/journal.pone.0221591 Text en © 2019 Oosterom et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Oosterom, Natanja
de Jonge, Robert
Smith, Desiree E. C.
Pieters, Rob
Tissing, Wim J. E.
Fiocco, Marta
van Zelst, Bertrand D.
van den Heuvel-Eibrink, Marry M.
Heil, Sandra G.
Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia
title Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia
title_full Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia
title_fullStr Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia
title_full_unstemmed Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia
title_short Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia
title_sort changes in intracellular folate metabolism during high-dose methotrexate and leucovorin rescue therapy in children with acute lymphoblastic leukemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748431/
https://www.ncbi.nlm.nih.gov/pubmed/31527879
http://dx.doi.org/10.1371/journal.pone.0221591
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