Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

Abstract

Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

Leucovorin (folinic acid) rescue for high‐dose methotrexate: A review

“…For ALL, measurements of MTX plasma concentrations and planned leucovorin rescue (15-50 mg/m 2 every 6 h) were usually performed at 36-54 h after the start of MTX infusion (the MTX doses ranged from 2.85 to 8 g/m 2 ). 9,13,20,[26][27][28][29][30][31] For lymphoma, the measurements of MTX plasma concentrations and planned leucovorin rescue (15-25 mg/m 2 or 30-100 mg every 6 h) were usually performed at 18-48 h after the start of MTX infusion (the MTX doses ranged from 2 to 8 g/m 2 ). [32][33][34] For osteosarcoma, the measurements of MTX plasma concentrations and planned leucovorin rescue (15 mg/m 2 or 10-12 mg every 6 h) were usually performed at 6-24 h after the start of MTX infusion (the MTX doses ranged from 10 to 12 g/m 2 ).…”

“…[32][33][34] For osteosarcoma, the measurements of MTX plasma concentrations and planned leucovorin rescue (15 mg/m 2 or 10-12 mg every 6 h) were usually performed at 6-24 h after the start of MTX infusion (the MTX doses ranged from 10 to 12 g/m 2 ). [35][36][37] If MTX plasma concentrations were not within the expected range, augmented leucovorin rescue was performed at 42 h to 54 h for ALL, 9,13,20,[26][27][28][29][30][31] at 48 h to 72 h for lymphoma, [32][33][34] and at 24 h to 72 h for osteosarcoma 36,38,39 after the start of MTX infusion.…”

“…For osteosarcoma, the dosage of MTX is commonly 8-12 g/m 2 , and the leucovorin initiation time is 24 h. 9,15 ALL have the largest amount of literature among the three tumour types for leucovorin rescue, and the rescue plan was relatively complete. 9,13,20,[26][27][28][29][30][31] More attention should be given to leucovorin rescue in patients with osteosarcoma and lymphoma.…”

“…At 42 h after 5 g/m 2 HDMTX infusion comedicated with 6-mercaptopurine or other drugs, Schrappe et al 13 and Möricke et al 30 gave an additional dose (not specified) when the MTX concentration exceeded 1.0 μmol/L. Niinimaki et al 26…”

“…24 At present, various methods for calculating leucovorin doses in different tumour types have been proposed, including empirical calculations based on MTX plasma concentrations, 25 the Bleyer nomogram, 14 and other methods. 26 Nonetheless, leucovorin rescue protocols differ greatly across tumour types and medical institutions.…”