What are the recommended clinical guidelines for initiating and titrating leucovorin rescue in patients receiving high‑, intermediate‑, or low‑dose methotrexate, including adjustments for impaired renal function, when a FRATT test is unavailable?

Leucovorin Initiation and Dose Escalation Without FRATT Testing

For high-dose methotrexate (12-15 g/m²), start leucovorin at 15 mg IV/PO every 6 hours beginning 24 hours after the start of methotrexate infusion, and escalate to 150 mg IV every 3 hours if serum methotrexate remains ≥50 µmol/L at 24 hours or ≥5 µmol/L at 48 hours, or if serum creatinine doubles within 24 hours. 1

Standard High-Dose Methotrexate Leucovorin Rescue Protocol

Initial Dosing for Normal Elimination

• Begin leucovorin 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses starting exactly 24 hours after the beginning of methotrexate infusion 1
• This timing is critical: starting at 24 hours is safe and effective, whereas delays beyond 36-42 hours significantly increase toxicity risk 2, 3
• Administer parenterally (IV or IM) if gastrointestinal toxicity, nausea, or vomiting is present 1

Monitoring Requirements to Guide Dose Escalation

• Measure serum creatinine and methotrexate levels at least once daily 1
• Expected normal elimination: methotrexate approximately 10 µmol/L at 24 hours, 1 µmol/L at 48 hours, and <0.2 µmol/L at 72 hours 1
• Continue hydration and urinary alkalinization (pH ≥7.0) until methotrexate level falls below 0.05 µmol/L 1

Dose Escalation Algorithm Based on Methotrexate Levels and Renal Function

Delayed Late Elimination (Moderate Risk)

• If methotrexate remains >0.2 µmol/L at 72 hours or >0.05 µmol/L at 96 hours: Continue leucovorin 15 mg every 6 hours until methotrexate <0.05 µmol/L 1
• This represents delayed but not dangerous elimination requiring extended standard dosing 1

Delayed Early Elimination with Acute Renal Injury (High Risk)

Escalate immediately to leucovorin 150 mg IV every 3 hours if ANY of the following occur: 1

• Methotrexate ≥50 µmol/L at 24 hours after administration
• Methotrexate ≥5 µmol/L at 48 hours after administration
• Serum creatinine increases ≥100% within 24 hours (e.g., 0.5 mg/dL rising to ≥1.0 mg/dL)

Continue 150 mg IV every 3 hours until methotrexate <1 µmol/L, then reduce to 15 mg IV every 3 hours until methotrexate <0.05 µmol/L 1

Additional Supportive Measures for Severe Toxicity

• Aggressive IV hydration and urinary alkalinization are mandatory to prevent methotrexate precipitation in renal tubules 1
• Monitor fluid and electrolyte status closely until renal failure resolves 1
• Consider hemodialysis combined with charcoal hemoperfusion for life-threatening toxicity with severe renal failure 4

Low-Dose Methotrexate Toxicity Management

For Inadvertent Overdose or Severe Toxicity

Administer leucovorin immediately upon recognition—efficacy is time-critical and diminishes dramatically after 24 hours 5, 6

Initial dosing: 5, 6

• Standard dose: 15 mg IV or PO every 6 hours
• If methotrexate level unknown or severe toxicity suspected: up to 100 mg/m² IV initially
• Continue every 6 hours until clinical recovery

For severe toxicity (WBC <1×10⁹/L, severe mucositis, or organ dysfunction): 6

• Escalate to leucovorin 100 mg/m² IV every 3 hours until methotrexate level <10⁻⁸ M
• Add filgrastim (G-CSF) 5 µg/kg subcutaneously daily for severe neutropenia 5

Evidence on Dose Comparison

• A 2023 randomized trial comparing 15 mg vs 25 mg leucovorin every 6 hours for severe low-dose methotrexate toxicity found no difference in 30-day mortality (42% vs 47%) or hematological recovery 7
• This suggests standard 15 mg dosing is adequate for low-dose toxicity, with escalation reserved for high-dose scenarios 7

Gestational Trophoblastic Neoplasia: 8-Day Methotrexate Regimen

For the 8-day methotrexate protocol (1.0-1.5 mg/kg IM every other day × 4 doses): 8

• Administer leucovorin 15 mg PO alternating with methotrexate doses (given on days 2,4,6,8)
• This is a fixed-dose rescue protocol, not requiring escalation based on levels 8
• Repeat cycle every 2 weeks with hCG monitoring 8

Critical Timing Considerations

When Leucovorin Can Be Safely Delayed

• For high-dose methotrexate (5-6 g/m²), leucovorin rescue can be safely started at 30-36 hours if serum methotrexate levels remain consistently low at 24,30, and 36 hours 2
• Rescue delayed to 42-48 hours results in considerable toxicity except with very low MTX doses (1 g/m²) 2
• In the absence of FRATT testing, do not delay beyond 36 hours from methotrexate start 2

When Earlier Rescue May Be Needed

• Patients with renal insufficiency (CrCl <60 mL/min) require earlier intervention and lower thresholds for dose escalation 5, 6
• Third-space fluid collections (pleural effusions, ascites) mandate enhanced vigilance and lower escalation thresholds 6
• Advanced age (>70 years) increases toxicity risk and warrants closer monitoring 5

Common Pitfalls to Avoid

Never confuse folic acid with folinic acid (leucovorin): 5

• Only leucovorin bypasses methotrexate's metabolic block
• Folic acid is for prevention; leucovorin is for treatment of acute toxicity

Do not administer leucovorin intrathecally—this is contraindicated 1

Do not assume low serum methotrexate levels exclude toxicity: 5

• Treat based on clinical presentation (mucositis, cytopenias, renal dysfunction)
• Serum levels guide duration but not necessarily initiation of rescue

Avoid NSAIDs during and after methotrexate administration: 5

• NSAIDs reduce renal methotrexate elimination and dramatically increase toxicity risk
• This interaction is dangerous at any methotrexate dose

Adjunctive Measures

Maintain aggressive supportive care throughout rescue: 1

• IV hydration at 3 L/day minimum
• Urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0
• Daily monitoring of CBC with differential, renal function, and liver enzymes 5, 6

For severe bone marrow suppression: 5

• Filgrastim 5 µg/kg subcutaneously daily accelerates myeloid recovery
• Monitor closely for sepsis—mortality risk is substantial with severe myelosuppression