Third-Space Entrapment of Methotrexate in Anthracycline-Induced Cardiomyopathy: The First Complete Case Trajectory From Toxicity to Rescue Failure

Methotrexate (MTX) is vital for treating multiple malignancies, including central nervous system (CNS) hematologic malignancies, but toxicity is a major limitation. Anthracyclines, cornerstones of lymphoma therapy, can cause cardiomyopathy, which may alter drug kinetics. This case highlights catastrophic MTX toxicity precipitated by prior anthracycline-induced cardiomyopathy. A 64-year-old with diffuse large B-cell lymphoma (DLBCL) and anthracycline-induced cardiotoxicity was admitted for CNS-directed MTX therapy. Despite standard prophylaxis and prior tolerance, the patient developed anuria, hypotension, and cardiogenic shock following infusion. Serum MTX peaked at >600 μmol/L. Bedside imaging revealed a reduced ejection fraction and a large pleural effusion. Despite receiving glucarpidase and high-flux dialysis, MTX levels remained persistently elevated. Thoracentesis confirmed third-space sequestration with pleural MTX levels of 89 μmol/L. Clearance required 35 days of continuous dialysis and leucovorin rescue before levels fell below 0.1 μmol/L. The patient suffered cardiogenic shock and encephalopathy before transitioning to comfort care. This case illustrates how anthracycline-induced cardiomyopathy potentiates MTX toxicity through three mechanisms: decreased systemic circulation, cardiorenal syndrome-mediated reduced excretion, and increased third-space sequestration due to venous stasis. These factors trigger a deleterious cycle of multi-organ failure. This trajectory underscores the role of cardiomyopathy-induced effusions as reservoirs for third-space entrapment, which creates a pharmacological barrier leading to definitive rescue failure despite aggressive systemic detoxification and high-flux hemodialysis. Clinicians must recognize cardiomyopathy as a critical risk factor for MTX sequestration and toxicity, regardless of whether prior cycles were tolerated. Early recognition of third-spacing and multidisciplinary management are essential to improve outcomes in high-risk cardio-oncology patients.