What is a leukovorin (folinic acid) rescue in medical treatment?

What is Leucovorin Rescue?

Leucovorin rescue is a life-saving antidote strategy that provides reduced folates (folinic acid) to bypass methotrexate's toxic blockade of dihydrofolate reductase in normal cells, allowing DNA synthesis to resume while maintaining antitumor effects—it must be initiated within 24 hours of high-dose methotrexate administration to prevent potentially fatal toxicity. 1, 2, 3

Mechanism and Rationale

Leucovorin rescue exploits a critical difference between normal and malignant cells:

• Normal cells can utilize leucovorin at low doses through active transport systems to bypass methotrexate's metabolic block 4
• Tumor cells (particularly osteosarcoma) rely primarily on passive diffusion and require much higher drug concentrations to achieve the same effect 4
• This differential allows high-dose methotrexate (3-8 g/m²) to achieve tumoricidal plasma concentrations while leucovorin selectively rescues normal tissues 2, 5

Critical Timing Requirements

Leucovorin is most effective when initiated within hours of the last methotrexate dose, with efficacy decreasing dramatically over time and becoming doubtful if started later than 24 hours after methotrexate administration. 6, 3

• For inadvertent overdose or delayed excretion, leucovorin rescue should begin as soon as possible and within 24 hours of methotrexate administration 3
• Early treatment may be life-saving given the high mortality risk associated with methotrexate overdose 6

Standard Dosing Protocols

Initial Rescue Dosing

• Standard dose: Leucovorin 15 mg (10 mg/m²) administered IV, IM, or PO every 6 hours until serum methotrexate level falls below 10⁻⁸ M (0.01 micromolar) 3
• Overdose situation: Up to 100 mg/m² IV if methotrexate level is unknown 6
• Oral doses greater than 25 mg are not recommended due to saturable absorption—parenteral administration is required for higher doses 3

Dose Escalation Criteria

If the 24-hour serum creatinine increases 50% over baseline, or if methotrexate levels remain elevated (>5 × 10⁻⁶ M at 24 hours or >9 × 10⁻⁷ M at 48 hours), increase leucovorin to 150 mg (100 mg/m²) IV every 3 hours until methotrexate level drops below 10⁻⁸ M. 3

• In critical cases with retarded elimination, leucovorin doses must be tenfold higher than the actual amount of methotrexate in the body system 4
• The formula: Leucovorin (mg) = 10 × MTX (mg/L) × 0.76 × body weight (kg) 4

Essential Supportive Measures

Leucovorin rescue must be combined with aggressive supportive care:

• Hydration: 3 L/day or 125 mL/m²/hr IV 1, 3
• Urinary alkalinization: Maintain urine pH ≥7.0 using sodium bicarbonate, continued until methotrexate level <0.05 micromolar 1, 3
• Monitoring: Serum creatinine and methotrexate levels at least once daily, with more frequent monitoring in complicated cases 1, 3

Context-Specific Regimens

Different malignancies require tailored approaches:

• Low-risk gestational trophoblastic neoplasia (methotrexate 50 mg IM): Leucovorin 15 mg orally 30 hours after each injection 1
• High-risk gestational trophoblastic neoplasia (methotrexate 300 mg/m² over 12 hours): Leucovorin 15 mg IV/PO every 12 hours for 4 doses, starting 24 hours after methotrexate infusion 1
• Acute lymphoblastic leukemia (methotrexate 1 g/m² over 24 hours): Leucovorin 10 mg/m² starting at 42 hours, repeated every 6 hours for 3 doses 1
• Osteosarcoma: High-dose methotrexate with leucovorin rescue is standard, though exact contribution to efficacy remains debated 7, 5

Management of Severe Toxicity

For patients with gastrointestinal toxicity, nausea, or vomiting, leucovorin must be administered parenterally rather than orally 3

Additional interventions for severe cases:

• G-CSF (filgrastim): 5 mcg/kg/day subcutaneously for toxic bone marrow suppression 1, 6
• Activated charcoal: If ≥1 mg/kg methotrexate ingested within 1 hour 1, 6
• Hospital admission: Required for monitoring and sepsis surveillance due to high mortality risk 1, 6
• Carboxypeptidase G2: Consider if methotrexate levels remain persistently elevated despite standard measures 2

Common Pitfalls

The usual leucovorin dose is insufficient for effective bone marrow rescue when methotrexate serum concentration equals or exceeds 10⁻⁶ M. 4

• Leucovorin overrescue can reduce both toxicity AND antitumor effect—progressive increases in leucovorin dosage diminish therapeutic benefit 8
• Patients with delayed methotrexate elimination will develop reversible nonoliguric renal failure requiring extended rescue therapy and close monitoring until methotrexate falls below 0.05 micromolar and renal function recovers 3
• Consider drug interactions that may interfere with methotrexate elimination or serum albumin binding when toxicities occur 3

Adjunctive Measures

For prolonged high methotrexate levels with persistent toxicity:

• Thymidine rescue: 8 g/m²/day continuous IV infusion can be combined with high-dose leucovorin (1,200 mg/day) for severe cases 9
• Topical leucovorin: Eye drops and mouth washes may prevent conjunctivitis and mucositis when methotrexate levels remain >2.4 micromolar for extended periods 9
• MTHFR genotyping: Recommended for patients requiring additional cycles after prolonged high methotrexate levels to identify those at increased toxicity risk 2