Abstract
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.
Highlights
After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients
red blood cell (RBC) MTX-PG and folate levels We measured RBC MTX-PG levels at start of protocol M, which is a week before start of HD-MTX, in 8 patients (Table 2) and observed that low levels of MTXPG2–5 were present (median 7.5 nmol/L, interquartile range (IQR) 4.2–9.2)
No decrease or less steep increase of RBC MTX was observed compared to RBC folate levels, which was expected if a large competition for cellular transport mechanisms would have been the case
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. MTX is an antifolate that impairs purine- and thymidine synthesis by inhibiting the Oosterom et al BMC Cancer (2020) 20:940 Both pediatric ALL studies [8, 10,11,12] and rheumatoid arthritis (RA) studies [13, 14] have shown that the administration of folate rescue therapy decreases toxicity, but might decrease treatment efficacy – reflected by a higher risk of relapse in ALL and a higher disease activity in RA. Several studies advocate the use of higher LV doses to reduce toxicity as they were not able to show decreased treatment efficacy by LV rescue after HD-MTX [15,16,17]. We prospectively determined red blood cell (RBC) folate and MTX levels longitudinally after each of the four consecutive 2-weekly 5 g/m2 HD-MTX courses with LV rescue in pediatric ALL patients to assess the changes in RBC folate and MTX levels over time
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