The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia

After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hyp...

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Published in:	BMC cancer Vol. 20; no. 1; pp. 940 - 10
Main Authors:	Oosterom, N, Fiocco, M, Kloos, R Q H, van der Sluis, I M, Pieters, R, van Zelst, B D, Smith, D E C, van den Heuvel-Eibrink, M M, de Jonge, R, Heil, S G
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 30-09-2020 BioMed Central BMC
Subjects:	Acids Acute lymphoblastic leukemia Acute lymphocytic leukemia Adolescent Analysis Antimetabolites, Antineoplastic - administration & dosage Antimetabolites, Antineoplastic - blood Blood tests Care and treatment Child Child, Preschool Children Chromatography, Liquid Dihydrofolate reductase Enzymes Erythrocytes Erythrocytes - drug effects Female Folic acid Folic Acid - blood Folinic acid High definition television Humans Infant Informed consent Leucovorin Leucovorin - administration & dosage Leucovorin - blood Leukemia Lymphatic leukemia Male Methotrexate Methotrexate - administration & dosage Methotrexate - blood Mucositis Patient admissions Patients Pediatric oncology Pediatrics Physiological aspects Plasma Precursor Cell Lymphoblastic Leukemia-Lymphoma - blood Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Tandem Mass Spectrometry Treatment Outcome Vitamin B Pediatric oncology Leucovorin Acute lymphoblastic leukemia Methotrexate
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Summary:	After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake. We prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m /dose) and Leucovorin (15 mg/m /dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time. Both RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8-165.2) after which levels plateaued during the 3 and 4th course (until median 141.3 nmol/L, IQR 100.2-190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3-594.2) after which levels plateaued during the 3 and 4th course (until median 411.5 nmol/L, IQR 240.3-665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG. These results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary.
ISSN:	1471-2407 1471-2407
DOI:	10.1186/s12885-020-07422-y