What is the recommended dose of Leucovorin (folinic acid) for a patient with methotrexate-induced pancytopenia?

Leucovorin Dosing for Methotrexate-Induced Pancytopenia

For methotrexate-induced pancytopenia, immediately discontinue methotrexate and administer leucovorin at an initial dose of up to 100 mg/m² IV, then continue with 15 mg IV every 6 hours until hematological abnormalities resolve. 1, 2

Immediate Management Protocol

Time is critical—leucovorin is most effective when initiated within hours of the last methotrexate dose, with efficacy decreasing dramatically after 24 hours. 1 Early treatment may be life-saving given the high mortality risk (42-47% in severe cases). 3, 4

Initial Dosing Strategy

• Start with up to 100 mg/m² IV if methotrexate levels are unknown 1, 2, 5
• Then continue with 15 mg IV every 6 hours until methotrexate level falls below 0.05 micromolar and hematological parameters normalize 1, 2, 5
• A randomized controlled trial found no survival benefit from higher doses (25 mg vs 15 mg every 6 hours), so the standard 15 mg dose is appropriate 4

Severity-Based Adjustments

For severe pancytopenia (WBC <2,000 cells/mm³, Hb <10 g/dL, platelets <50,000 cells/mm³):

• Admit immediately for close monitoring 2
• If methotrexate level is ≥50 micromolar at 24 hours or ≥5 micromolar at 48 hours, escalate to 150 mg IV every 3 hours until level drops below 1 micromolar, then 15 mg IV every 3 hours until below 0.05 micromolar 5
• Consider adding filgrastim (G-CSF) 5 mcg/kg/day subcutaneously to accelerate myeloid recovery 1, 2

Critical Supportive Measures

Aggressive IV hydration (3 L/day) and urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 are essential to enhance methotrexate elimination. 1, 2, 5 These measures prevent methotrexate precipitation in renal tubules and facilitate drug clearance. 5, 6

Monitoring Requirements

• Monitor complete blood count frequently until recovery 2
• Check serum creatinine and methotrexate levels at least daily 5
• Continue leucovorin until methotrexate level is below 0.05 micromolar (5 x 10⁻⁸ M) AND hematological abnormalities have resolved 1, 2, 5
• Monitor for sepsis, as infection is a major cause of mortality in these patients 1, 3

Common Pitfalls to Avoid

Do not administer leucovorin intrathecally—this is explicitly contraindicated. 5 The parenteral route (IV preferred) must be used, especially in the presence of gastrointestinal toxicity, nausea, or vomiting. 5

White blood cell count at admission is the most important prognostic factor for survival—patients with WBC <2,000 cells/mm³ have significantly higher mortality. 3 Hypoalbuminemia is also a strong predictor of poor outcome. 4

Key Risk Factors Present in This Case

The most common contributing factors in methotrexate-induced pancytopenia include:

• Renal insufficiency (present in 30% of cases) 3
• Dosing errors, particularly daily instead of weekly administration (28% of cases) 3
• Lack of folate supplementation (15% of cases) 3
• Drug interactions with NSAIDs, trimethoprim-sulfamethoxazole, penicillins, or salicylates 2, 3

Duration of Therapy

Leucovorin rescue typically continues for 10 doses (60 hours) in standard cases, but must be extended until both methotrexate levels and blood counts normalize. 5 In severe toxicity cases, methotrexate levels may remain elevated for 7-17 days, requiring prolonged leucovorin administration. 7

High-dose leucovorin as sole therapy (without hemodialysis or other extracorporeal removal) has been shown effective even with methotrexate levels >100 micromolar at 24 hours, though with significant morbidity including neutropenia lasting 1-5 days and thrombocytopenia lasting 5-10 days. 7