Abstract
BackgroundMethotrexate (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.MethodsWe 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.ResultsErythrocyte 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.ConclusionIntracellular 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.
Highlights
Intracellular folate levels accumulate after High-dose methotrexate (HD-MTX) and Leucovorin therapy in children with acute lymphoblastic leukemia (ALL), suggesting that Leucovorin restores the intracellular folate pool
Others have successfully introduced early LV rescue in individualized doses after MTX in treatment protocols with high event-free survival rates. [19,20,21] In addition, previous studies failed to detect correlations between red blood cell (RBC) MTX and folate levels measured at end of intensification therapy and throughout maintenance therapy in relation to complete continuous remission and eventfree survival rates. [8, 21] These contradictory study results emphasize the difficulties still encountered in understanding the impact in Leucovorin and MTX on pediatric ALL treatment outcome
This study aims to determine whether serum and intracellular folate levels accumulate during four consecutive HD-MTX and Leucovorin courses in children with ALL
Summary
High-dose methotrexate (HD-MTX) is an important component of pediatric acute lymphoblastic leukemia (ALL) treatment. [1,2,3] Methotrexate is a cytotoxic agent that depletes intracellular reduced folate levels by inhibiting the enzymes Dihydrofolate Reductase (DHFR) and Thymidylate Synthase (TYMS) (Fig 1). [4,5,6] MTX thereby inhibits DNA- and RNA synthesis. [4,5,6] After HD-MTX infusions, folinic acid rescue therapy (Leucovorin) is administered to reduce toxic side effects of therapy. [7]Previous studies showed that red blood cell folate levels have been low in patients treated with only MTX without Leucovorin. [8,9,10] Leucovorin and MTX are structural analogues and could compete for cellular transport-, polyglutamylation-, and enzyme-binding (DHFR/TS) mechanisms. [11, 12] As a reduced folate, Leucovorin could bypass the enzyme DHFR during consecutive HD-MTX and LV courses, thereby restoring purine- and pyrimidine- synthesis. This phenomenon has been referred to as the folate ‘overrescue’ principle, where healthy cells, and tumor cells are ‘rescued’ from cell death due to Leucovorin after HD-MTX Both in pediatric ALL studies [13,14,15,16] as in rheumathoid arthritis studies [17, 18] results suggested that Leucovorin rescue therapy decreases toxicity rates, but showed an increased risk of relapse in ALL and decreased treatment efficacy in RA. [8, 21] These contradictory study results emphasize the difficulties still encountered in understanding the impact in Leucovorin and MTX on pediatric ALL treatment outcome. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX
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