What is the recommended dosing regimen for leucovorin (folinic acid) rescue after high-dose methotrexate therapy?

Leucovorin Rescue After High-Dose Methotrexate

For high-dose methotrexate therapy (≥12 g/m²), initiate leucovorin rescue at 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses starting 24 hours after the beginning of methotrexate infusion. 1, 2

Standard Dosing Protocol

The FDA-approved regimen for leucovorin rescue following high-dose methotrexate (12-15 g/m² over 4 hours) is:

• Start time: 24 hours after beginning methotrexate infusion 1, 2
• Dose: 15 mg every 6 hours 1, 2
• Duration: 10 doses (60 hours total) 1, 2
• Route: Oral, intramuscular, or intravenous (use parenteral route if gastrointestinal toxicity, nausea, or vomiting present) 1

Critical warning: Never administer leucovorin intrathecally 1, 2

Dose Escalation Based on Methotrexate Levels

Leucovorin dosing must be adjusted based on serum methotrexate levels and renal function. The following algorithm guides dose escalation 1, 2:

Normal Methotrexate Elimination

• Methotrexate levels: ~10 micromolar at 24 hours, 1 micromolar at 48 hours, <0.2 micromolar at 72 hours 1, 2
• Leucovorin: Continue standard 15 mg every 6 hours for 60 hours 1, 2

Delayed Late Methotrexate Elimination

• Methotrexate levels: >0.2 micromolar at 72 hours AND >0.05 micromolar at 96 hours 1, 2
• Leucovorin: Continue 15 mg every 6 hours until methotrexate level <0.05 micromolar 1, 2

Delayed Early Methotrexate Elimination or Acute Renal Injury

• Methotrexate levels: ≥50 micromolar at 24 hours OR ≥5 micromolar at 48 hours 1, 2
• OR creatinine: ≥100% increase at 24 hours (e.g., 0.5 mg/dL to ≥1.0 mg/dL) 1, 2
• Leucovorin: 150 mg IV every 3 hours until methotrexate <1 micromolar, then 15 mg IV every 3 hours until methotrexate <0.05 micromolar 1, 2

Essential Supportive Measures

Leucovorin rescue must be accompanied by aggressive supportive care 1, 2:

• Hydration: Continue aggressive IV hydration (3 L/day or 125 ml/m²/hr) 3, 4
• Urinary alkalinization: Maintain urine pH ≥7.0 using sodium bicarbonate 1, 3
• Monitoring: Measure serum creatinine and methotrexate levels at least once daily 1
• Duration: Continue hydration and alkalinization until methotrexate level <5 × 10⁻⁸ M (0.05 micromolar) 1

For patients with delayed early elimination, these supportive measures are critical as reversible renal failure is likely, requiring close monitoring of fluid and electrolyte status 1, 2

Context-Specific Regimens

Low-Risk Gestational Trophoblastic Neoplasia

For lower-dose methotrexate (50 mg IM every 48 hours × 4 doses) 5:

• Leucovorin: 15 mg orally 30 hours after each methotrexate injection 5

High-Risk Gestational Trophoblastic Neoplasia (EMA/CO Regimen)

For methotrexate 300 mg/m² IV over 12 hours 5:

• Leucovorin: 15 mg IV or orally every 12 hours for 4 doses, starting 24 hours after commencing methotrexate infusion 5

Acute Lymphoblastic Leukemia (Limited Resources)

For intermediate-dose methotrexate (1 g/m² over 24 hours) 5:

• Leucovorin: 10 mg/m² starting at 42 hours, repeated every 6 hours for 3 doses 5
• Increase leucovorin rescue based on elevated serum creatinine 5

Intrathecal Methotrexate

For patients receiving intrathecal methotrexate 6:

• Leucovorin: 10 mg orally twice daily beginning on day of treatment, continuing for 3 days 6

Critical Pitfalls to Avoid

Timing is everything: Leucovorin efficacy decreases dramatically with delayed initiation. The British Journal of Dermatology emphasizes that leucovorin is most effective within hours of the last methotrexate dose, with doubtful efficacy if started >24 hours after the last dose 3. For inadvertent overdose, initiate leucovorin immediately upon recognition, with doses up to 100 mg/m² IV if methotrexate level is unknown 3.

Do not under-rescue: In critical cases with retarded methotrexate elimination, rescue requires leucovorin doses tenfold higher than the actual amount of methotrexate in the body system 7. The formula: Leucovorin (mg) = 10 × MTX (mg/L) × 0.76 × body weight (kg) 7.

Monitor for drug interactions: Always reconsider whether the patient is taking medications that interfere with methotrexate elimination or serum albumin binding when laboratory abnormalities or clinical toxicities are observed 1.

Extended rescue for subclinical toxicity: If significant clinical toxicity is observed despite less severe laboratory abnormalities, extend leucovorin rescue for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses 1.

Settings Without Methotrexate Level Monitoring

In resource-limited settings without access to methotrexate levels, safe administration is possible using 4:

• Extended hydration: 125 ml/m²/hr for 72 hours (vs. standard 30 hours) 4
• Additional leucovorin: 6 doses of 15 mg/m² instead of 3 doses 4
• Monitoring: Serum creatinine and urine pH at baseline, 24, and 48 hours 4
• Dose adjustment: Increase hydration to 200 ml/m²/hr if creatinine >1.25× baseline 4

This approach was validated in 100 cycles of high-dose methotrexate (3-5 g/m²) with acceptable toxicity profiles 4.

Severe Toxicity Management

For inadvertent methotrexate overdose or severe toxicity 3:

• Hospital admission: Required for monitoring 3
• Activated charcoal: If ≥1 mg/kg ingested within 1 hour, give before leucovorin 3
• G-CSF: Filgrastim 5 mcg/kg/day subcutaneously for toxic bone marrow suppression 3
• Sepsis monitoring: High mortality risk necessitates vigilant infection surveillance 3

A recent randomized trial found no survival difference between 15 mg vs. 25 mg leucovorin every 6 hours for severe low-dose methotrexate toxicity, with 30-day mortality of 42-47% in both groups 8. Serum albumin was the only predictor of survival 8, underscoring that leucovorin alone cannot overcome severe toxicity from delayed presentation.