The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leuke
- PDF / 1,701,792 Bytes
- 10 Pages / 595.276 x 790.866 pts Page_size
- 67 Downloads / 205 Views
RESEARCH ARTICLE
Open Access
The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia N. Oosterom1,2* , M. Fiocco1,3,4, R. Q. H. Kloos5, I. M. van der Sluis1, R. Pieters1, B. D. van Zelst2, D. E. C. Smith6, M. M. van den Heuvel-Eibrink1, R. de Jonge6 and S. G. Heil2
Abstract Background: 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. Methods: 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/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. Results: Both 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. Conclusion: 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. Keywords: Methotrexate, Leucovorin, Acute lymphoblastic leukemia, Pediatric oncology
Background High-dose Methotrexate (HD-MTX) is an important component of pediatric acute lymphoblastic leukemia (ALL) treatment [1–3]. MTX is an antifolate that impairs purine- and thymidine synthesis by inhibiting the * Correspondence: [email protected] 1 Princess Máxima Center for Pediatric Oncology, Postbus 113, 3720 AC Bilthoven, Utrecht, The Netherlands 2 Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Full list of author information is available at the end of the article
enzymes Dihydrofolate Reductase (DHFR) and Thymidylate Synthase (TS) [4]. Following HD-MTX infusions, folinic acid rescue therapy (Leucovorin – LV) is administered to reduce toxic side effects of therapy. LV is a reduced folate that bypasses the block of DHFR by MTX (Fig. 1) [5]. Leucovorin and MTX are structural analogues, possi
Data Loading...
