New Recommendations for Reversal of High-dose Methotrexate Cytotoxicity with Folinic Acid

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2025 Mar 13

PMID 40075030

Authors

Jesper Heldrup

Archie Bleyer

Laura Ramsey

Lauren Schaff

Brooke Bernhardt

Stefan Schwartz

Etienne Chatelut

Miriam Hwang

Carolina Ten

Martin Guscott

Scott Howard

Affiliations

Soon will be listed here.

Abstract

Purpose: Folinic acid (FA) rescue protocols to counter the adverse effects of high-dose methotrexate (HDMTX) vary widely, and the risk of over-rescue and potential adverse effects of excessive FA (e.g., hypercalcemia) are under-recognized issues when providing augmented rescue in cases of delayed methotrexate elimination (DME). This opinion summary defines over-rescue, describes its potential adverse impacts, highlights the risk of hypercalcemia associated with excessive FA dosing in patients with acute kidney injury (AKI) from HDMTX, and provides recommendations to improve safety and efficacy of FA rescue in patients receiving HDMTX.

Methods: A multidisciplinary panel of experts with clinical experience in HDMTX treatment convened in three roundtable meetings to coalesce expert opinion and best published evidence on the pharmacology and clinical effects and interactions of FA and HDMTX.

Results: The type of FA (calcium folinate, calcium levofolinate, sodium levofolinate), dose, and frequency of FA administration may be factors for over-rescue and the development of hypercalcemia due to their respective pharmacokinetic characteristics, especially in cases of DME requiring augmented FA rescue.

Conclusion: Clinicians are reminded of the possibility of over-rescue with FA and its impact on subsequent HDMTX courses, types of FA available and their durations of action, and avoid providing too frequent doses. In the setting of AKI and DME requiring high doses of FA, use of sodium levofolinate or calcium levofolinate may be considered to reduce the risk of hypercalcemia associated with calcium folinate.

References

Oosterom N, de Jonge R, Smith D, Pieters R, Tissing W, Fiocco M . Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia. PLoS One. 2019; 14(9):e0221591. PMC: 6748431. DOI: 10.1371/journal.pone.0221591. View

Schilsky R, Choi K, Vokes E, Guaspari A, Guarnieri C, Whaling S . Clinical pharmacology of the stereoisomers of leucovorin during repeated oral dosing. Cancer. 1989; 63(6 Suppl):1018-21. DOI: 10.1002/1097-0142(19890315)63:6+<1018::aid-cncr2820631305>3.0.co;2-s. View

Reiss S, Buie L, Adel N, Goldman D, Devlin S, Douer D . Hypoalbuminemia is significantly associated with increased clearance time of high dose methotrexate in patients being treated for lymphoma or leukemia. Ann Hematol. 2016; 95(12):2009-2015. PMC: 5572815. DOI: 10.1007/s00277-016-2795-7. View

Schilsky R, Ratain M . Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. J Natl Cancer Inst. 1990; 82(17):1411-5. DOI: 10.1093/jnci/82.17.1411. View

Widemann B, Schwartz S, Jayaprakash N, Christensen R, Pui C, Chauhan N . Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy. Pharmacotherapy. 2013; 34(5):427-39. PMC: 3990659. DOI: 10.1002/phar.1360. View

Borsi J, Sagen E, Romslo I, MOE P . Rescue after intermediate and high-dose methotrexate: background, rationale, and current practice. Pediatr Hematol Oncol. 1990; 7(4):347-63. DOI: 10.3109/08880019009033412. View

Ratti M, Hahne J, Toppo L, Castelli E, Petrelli F, Passalacqua R . Major innovations and clinical applications of disodium-levofolinate: a review of available preclinical and clinical data. Ther Adv Med Oncol. 2019; 11:1758835919853954. PMC: 6552345. DOI: 10.1177/1758835919853954. View

Ferrari S, Bielack S, Smeland S, Longhi A, Egerer G, Hall K . EURO-B.O.S.S.: A European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma. Tumori. 2017; 104(1):30-36. DOI: 10.5301/tj.5000696. View

Marina N, Smeland S, Bielack S, Bernstein M, Jovic G, Krailo M . Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016; 17(10):1396-1408. PMC: 5052459. DOI: 10.1016/S1470-2045(16)30214-5. View

10.

Kinoshita A, Kurosawa Y, Kondoh K, Suzuki T, Manabe A, Inukai T . Effects of sodium in hydration solution on plasma methotrexate concentrations following high-dose methotrexate in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2003; 51(3):256-60. DOI: 10.1007/s00280-002-0565-9. View

11.

Ferrari S, Smeland S, Mercuri M, Bertoni F, Longhi A, Ruggieri P . Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol. 2005; 23(34):8845-52. DOI: 10.1200/JCO.2004.00.5785. View

12.

Skarby T, Anderson H, Heldrup J, Kanerva J, Seidel H, Schmiegelow K . High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia. 2006; 20(11):1955-62. DOI: 10.1038/sj.leu.2404404. View

13.

Jackson R, Liebich M, Berry P, Errington J, Liu J, Parker C . Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia-a report from the UKALL 2011 trial. Eur J Cancer. 2019; 120:75-85. DOI: 10.1016/j.ejca.2019.07.026. View

14.

Cohen I . Progression of osteosarcoma after high-dose methotrexate: over-rescue by folinic acid. Pediatr Hematol Oncol. 2003; 20(8):579-81. View

15.

Mckay C, Furman W . Hypercalcemia complicating childhood malignancies. Cancer. 1993; 72(1):256-60. DOI: 10.1002/1097-0142(19930701)72:1<256::aid-cncr2820720145>3.0.co;2-d. View

16.

Cohen I, Wolff J . How long can folinic acid rescue be delayed after high-dose methotrexate without toxicity?. Pediatr Blood Cancer. 2013; 61(1):7-10. DOI: 10.1002/pbc.24770. View

17.

NIXON P . Folinic acid: pharmacokinetics and pharmacodynamics. Clin Exp Pharmacol Physiol Suppl. 1979; 5:35-41. View

18.

Cohen I . Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect?. Cancer Chemother Pharmacol. 2017; 79(2):437. DOI: 10.1007/s00280-016-3234-0. View

19.

Straw J, Szapary D, Wynn W . Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res. 1984; 44(7):3114-9. View

20.

Cowan D, Tannock I . Factors that influence the penetration of methotrexate through solid tissue. Int J Cancer. 2001; 91(1):120-5. DOI: 10.1002/1097-0215(20010101)91:1<120::aid-ijc1021>3.0.co;2-y. View