What is the management of low-dose (LD) methotrexate (MTX) toxicity presenting with mucositis, leukopenia, and acute kidney injury (AKI)?

From the Guidelines

Management of low-dose methotrexate toxicity presenting with mucositis, leukopenia, and acute kidney injury requires immediate intervention with leucovorin (folinic acid) rescue therapy, as recommended by the British Association of Dermatologists' guidelines 1. The treatment should include administering leucovorin at 15-25 mg every 6 hours until serum methotrexate levels fall below 0.05 μmol/L or until clinical improvement occurs. Discontinue methotrexate immediately and provide aggressive supportive care including:

• IV hydration with isotonic fluids to maintain urine output above 100 mL/hour
• Urinary alkalinization with sodium bicarbonate to keep urine pH above 7
• Correction of electrolyte abnormalities For severe mucositis, provide oral care with:
• Saline rinses
• Topical anesthetics
• Pain management Granulocyte colony-stimulating factor (G-CSF) at 5-10 μg/kg/day subcutaneously may be administered for significant leukopenia. Monitor complete blood count, renal function, and electrolytes daily. Avoid medications that may compete with methotrexate for protein binding or impair its elimination, such as NSAIDs, sulfonamides, and probenecid. Glucarpidase (carboxypeptidase G2) at 50 units/kg IV may be considered for severe toxicity with high methotrexate levels and significant renal dysfunction, as suggested by the guidelines for overdose management 1. These interventions are critical because methotrexate toxicity results from excessive inhibition of dihydrofolate reductase, disrupting DNA synthesis in rapidly dividing cells, while leucovorin bypasses this blockade to rescue normal cells. Regular monitoring of patients on methotrexate, including full blood count, liver function tests, and urea and electrolytes, is essential to prevent toxicity, as outlined in the guidelines for safe and effective prescribing of methotrexate 1.

From the FDA Drug Label

Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion [see WARNINGS]. Leucovorin 15 mg (10 mg/m2) should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Serum creatinine and methotrexate levels should be determined at 24-hour intervals If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 x 10-6 M or the 48-hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 150 mg (100 mg/m2) IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate should be employed concomitantly.

The management of low-dose methotrexate toxicity presenting with mucositis, leukopenia, and acute kidney injury (AKI) involves:

• Leucovorin rescue: starting as soon as possible, with a dose of 15 mg (10 mg/m2) administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M.
• Parenteral administration: of leucovorin in the presence of gastrointestinal toxicity, nausea, or vomiting.
• Monitoring: of serum creatinine and methotrexate levels at 24-hour intervals.
• Adjustment of leucovorin dose: if the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 x 10-6 M or the 48-hour level is greater than 9 x 10-7 M.
• Hydration and urinary alkalinization: with sodium bicarbonate to maintain the urine pH at 7.0 or greater 2.

From the Research

Management of Low-Dose Methotrexate Toxicity

• The management of low-dose methotrexate (MTX) toxicity presenting with mucositis, leukopenia, and acute kidney injury (AKI) involves several key strategies 3, 4, 5, 6, 7.
• Clearance of MTX from the bloodstream: This is a primary goal in managing MTX toxicity, and it can be achieved through supportive measures such as hydration and sodium bicarbonate administration 5, 7.
• Folinic acid therapy: Leucovorin (folinic acid) is a commonly used antidote for MTX toxicity, and its optimum dose is unclear, varying from 15 to 25 mg every 6 hours 6.
• Organ treatment: Treatment of AKI, mucositis, and leukopenia is crucial in managing MTX toxicity, and high-dose leucovorin has been shown to be effective in reducing toxicity from MTX without the need for extracorporeal removal 5, 7.

Treatment of Severe MTX Toxicity

• Glucarpidase: This drug has been licensed for the treatment of high plasma MTX levels of >1 μmol/L in patients with compromised renal function who have delayed MTX elimination 3.
• High-dose leucovorin: This has been shown to be effective in reducing toxicity from MTX, and its use as a sole therapy for MTX toxicity has been reported 5, 7.
• Supportive care: This includes hydration, sodium bicarbonate administration, and monitoring of renal function, as well as treatment of mucositis, leukopenia, and other toxic manifestations 4, 5, 6, 7.

Monitoring and Prevention

• Monitoring of MTX levels: This is crucial in preventing and managing MTX toxicity, and serum MTX levels should be monitored regularly in patients receiving MTX therapy 3, 4, 5, 7.
• Dose adjustment: The dose of MTX should be adjusted according to renal function, and a lower initial dose should be considered in patients with renal deficiency 3.
• Patient education: Patients should be educated on the proper use of MTX, including the importance of taking the correct dose and frequency, and the potential risks of toxicity 3, 6.