What is the recommended use and dosage of leucovorin in patients receiving high-dose methotrexate therapy?

Leucovorin Rescue Protocol for High-Dose Methotrexate Therapy

For patients receiving high-dose methotrexate therapy, leucovorin rescue should be administered at 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses starting 24 hours after the beginning of methotrexate infusion, with dose adjustments based on methotrexate serum levels.

Standard Leucovorin Rescue Protocol

Dosing Schedule

• Standard protocol: 15 mg PO, IM, or IV every 6 hours for 60 hours (10 doses starting 24 hours after beginning methotrexate infusion) 1
• Administration route should be parenteral (IV) if gastrointestinal toxicity, nausea, or vomiting is present 1
• Do not administer leucovorin intrathecally under any circumstances 1

Monitoring and Dose Adjustments

Methotrexate levels and serum creatinine should be determined at least once daily, with leucovorin dosage adjusted based on the following guidelines 1, 2:

1. Normal methotrexate elimination:

   • Serum methotrexate ~10 μM at 24 hours, 1 μM at 48 hours, <0.2 μM at 72 hours
   • Continue standard dosing (15 mg every 6 hours)

2. Delayed late methotrexate elimination:

   • Serum methotrexate >0.2 μM at 72 hours or >0.05 μM at 96 hours
   • Continue 15 mg every 6 hours until methotrexate level <0.05 μM

3. Delayed early methotrexate elimination and/or acute renal injury:

   • Serum methotrexate ≥50 μM at 24 hours or ≥5 μM at 48 hours, OR
   • ≥100% increase in serum creatinine at 24 hours
   • Increase to 150 mg IV every 3 hours until methotrexate level <1 μM
   • Then 15 mg IV every 3 hours until methotrexate level <0.05 μM

Supportive Measures

Hydration and Urinary Alkalinization

• Maintain aggressive hydration (3-4 L/m²/day) and urinary alkalinization (pH >7.0) throughout treatment 2, 3
• Urinary alkalinization with sodium bicarbonate has been shown to decrease the incidence of acute nephrotoxicity and subsequent myelotoxicity 3

Extended Rescue

• If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy 1

Special Situations

Methotrexate Overdose

In case of overdose:

1. Administer activated charcoal if ingestion occurred within 1 hour
2. Immediately administer high-dose leucovorin (100 mg/m²)
3. Consider hemodialysis for extreme cases 2

Severe Renal Impairment

• Patients with delayed early methotrexate elimination are likely to develop reversible renal failure
• These patients require continuing hydration, urinary alkalinization, and close monitoring of fluid and electrolyte status until serum methotrexate level <0.05 μM and renal failure has resolved 1
• Consider glucarpidase in cases of significantly delayed elimination, particularly in patients with renal insufficiency 2

Low-Dose Methotrexate Toxicity

• For severe toxicity with low-dose methotrexate (≤50 mg/week), 15 mg IV leucovorin every 6 hours appears to be as effective as higher doses (25 mg) for rescue therapy 4

Important Considerations

Efficacy Concerns

• Progressive increases in leucovorin dosage can reduce both toxicity and the antitumor effect of methotrexate 5
• Delayed "low-dose" leucovorin rescue following high-dose methotrexate has been shown to be highly effective in preventing toxicity while maintaining antitumor effect 5

Monitoring Requirements

• Daily measurement of serum methotrexate levels until <0.05 μmol/L
• Monitor complete blood count, serum creatinine, and liver transaminases until normalization
• Most critical monitoring period is within the first 72 hours after administration 2

Contraindications

• Do not administer leucovorin intrathecally under any circumstances 1

By following this protocol and adjusting leucovorin dosing based on methotrexate levels and renal function, the risk of severe toxicity from high-dose methotrexate therapy can be significantly reduced while maintaining therapeutic efficacy.