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

BMC Cancer

R. de Jonge¹  D. E. C. Smith¹  B. D. van Zelst²  S. G. Heil²  R. Q. H. Kloos³  M. M. van den Heuvel-Eibrink⁴  R. Pieters⁴  I. M. van der Sluis⁴  N. Oosterom⁵  M. Fiocco⁶ 

[1] Department of Clinical Chemistry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands;Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia’s Children’s Hospital, Rotterdam, The Netherlands;Princess Máxima Center for Pediatric Oncology, Postbus 113, 3720 AC Bilthoven, Utrecht, The Netherlands;Princess Máxima Center for Pediatric Oncology, Postbus 113, 3720 AC Bilthoven, Utrecht, The Netherlands;Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;Princess Máxima Center for Pediatric Oncology, Postbus 113, 3720 AC Bilthoven, Utrecht, The Netherlands;Mathematical Institute, Leiden University, Leiden, The Netherlands;Department of Biomedical Data Sciences, Leiden University Medical Center, Medical Statistics, Leiden, The Netherlands;

关键词: Methotrexate;    Leucovorin;    Acute lymphoblastic leukemia;    Pediatric oncology;   

DOI  :  10.1186/s12885-020-07422-y

来源: Springer

【 摘 要 】

BackgroundAfter 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.MethodsWe 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/m2/dose) and Leucovorin (15 mg/m2/dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time.ResultsBoth RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2–5 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 3d 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 3d 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.ConclusionThese 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.

【 授权许可】

CC BY