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UK-VRX-2600029 Date of Last Revision: April 2026

MANAGEMENT of toxic
MTX concentrations

LEUCOVORIN rescue

For more than 30 years,
leucovorin rescue has been a cornerstone
of HDMTX treatment.¹
  • Limited effectiveness in the presence of high-circulating MTX concentrations (>10 mmol/L for 48 hours or longer)2
  • Excessive doses may impact the MTX efficacy at the next HDMTX course2
  • Leucovorin rescue is essential, but it does not clear MTX from the body

DIALYSIS-based methods

Haemofiltration, high-flux haemodialysis, charcoal haemoperfusion or haemofiltration, peritoneal dialysis, exchange transfusion, plasma exchange.²
  • Limited effectiveness in removing methotrexate and its metabolites3
  • Success rates highly variable3
  • Repeated cycles may be required due to rebound effect1,4
  • Methods not readily available outside of major medical centres3
  • Risks associated with the insertion of vascularaccess devices, transfusion of blood products, electrolyte imbalances3

Abbreviations: HDMTX, high dose methotrexate; MTX, methotrexate.

Patients who have one or more of the following risk factors may experience delayed MTX clearance1,2,5:

Nephrotoxic comedication (NSAIDs,PPIs,etc)
BMI >=25 kg/m2
Renal insufficiency priot to HDMTX (i.e. CrCl < 60 mL/min)
Prior toxicity with HDMTX
Adult and elderly patients, as many as 60% of whom may have some degree of renal disfunction
Third spacing (pleural effusions, ascites, intracranial fluid)
Volume depletion due to vomiting, diarrhea, or other factors
Polyuria
Urine pH<7

BMI, body mass index; CrCl, creatinine clearance; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.

References

  1. Howard SC, et al. Preventing and managing toxicities of high-dose methotrexate. Oncologist. 2016;21(12):1471-82.
  2. Ramsey LB, et al. Consensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. Oncologist. 2018;23(1):52-61.
  3. Widemann BC, et al. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer. 2004;100(10):2222-32.
  4. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11(6):694-703.
  5. Schwartz S, Borner K, Müller K, et al. Glucarpidase (carboxypeptidase G2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007;12:1299-1308.

UK-VRX-2600031 Date of Last Revision: February 2026