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 initiated 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. 1

Standard Leucovorin Rescue Protocol

The FDA-approved protocol for leucovorin rescue after high-dose methotrexate (12-15 g/m² administered over 4 hours) includes:

• Start leucovorin 24 hours after beginning methotrexate infusion
• Initial dose: 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses
• Continue until methotrexate level is below 0.05 micromolar
• Administer parenterally if gastrointestinal toxicity is present
• Do not administer leucovorin intrathecally 1

Dose Adjustment Based on Methotrexate Levels

Leucovorin dosing should be adjusted based on methotrexate elimination:

1. Normal Methotrexate Elimination:

   • Serum methotrexate ~10 micromolar at 24 hours, 1 micromolar at 48 hours, <0.2 micromolar at 72 hours
   • Continue 15 mg PO, IM, or IV every 6 hours for 60 hours (10 doses) 1

2. Delayed Late Methotrexate Elimination:

   • Serum methotrexate >0.2 micromolar at 72 hours, >0.05 micromolar at 96 hours
   • Continue 15 mg PO, IM, or IV every 6 hours until methotrexate level <0.05 micromolar 1

3. Delayed Early Methotrexate Elimination/Acute Renal Injury:

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

Supportive Care During Leucovorin Rescue

Aggressive supportive care is essential during leucovorin rescue:

• Maintain aggressive hydration (3-4 L/m²/day)
• Ensure urinary alkalinization (pH >7.0)
• Monitor serum creatinine and methotrexate levels at least once daily
• Continue hydration and alkalinization until methotrexate level <0.05 micromolar 2, 1

Special Considerations

For Patients with Delayed Elimination

• Patients with delayed early methotrexate elimination are likely to develop reversible renal failure
• Continue hydration, urinary alkalinization, and close monitoring of fluid and electrolyte status
• Consider extending leucovorin rescue for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses if significant clinical toxicity is observed 1

For Severe Toxicity

• High-dose leucovorin (up to 8 g/day) has been used successfully as sole therapy for methotrexate toxicity without the need for extracorporeal removal in patients with very high methotrexate levels 3
• Consider glucarpidase in cases of significantly delayed elimination, particularly in patients with renal insufficiency 2

Monitoring Requirements

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

Pitfalls and Caveats

• Do not administer leucovorin intrathecally under any circumstances 1
• Always consider potential drug interactions that may interfere with methotrexate elimination or binding to serum albumin 1
• L-leucovorin (the active isomer) at half the dose of racemic leucovorin has been shown to be equally effective for rescue therapy 4, 5
• For low-dose methotrexate toxicity, a dose of 15 mg leucovorin every 6 hours appears to be as effective as higher doses (25 mg) 6