Delayed methotrexate toxicity after initial clearance in a critically ill patient with severe fluid overload

Methotrexate (MTX) toxicity is a life-threatening complication in oncology patients. We report a 19-year-old male with newly diagnosed Burkitt lymphoma who received high-dose methotrexate as part of induction chemotherapy and initially met protocol-defined serum clearance criteria with suspected delayed MTX toxicity. This prolonged toxicity was due to possible redistribution from extravascular fluid compartments in the setting of severe fluid overload and renal dysfunction. Five weeks after methotrexate administration, a detectable serum methotrexate concentration (0.4 µmol/L) was identified despite no additional exposure. His course was complicated by tumor lysis syndrome, pleural effusions and anasarca, bowel perforations requiring multiple surgeries, acute respiratory distress syndrome, persistent pancytopenia, progressive renal and hepatic dysfunction, recurrent infections, and multiorgan failure. Despite treatment with leucovorin, urine alkalinization, continuous kidney replacement therapy, and high-flux hemodialysis, serum MTX concentrations demonstrated recurrent detectable elevations. This case highlights how altered pharmacokinetics in critical illness may render serum clearance thresholds unreliable and underscores the need for heightened clinical suspicion for delayed drug toxicity in critically ill patients with dynamic volume shifts or unexplained multiorgan dysfunction.