P2.103: Rebound Effect: The Under-Recognized Risk of Methotrexate Redistribution

Introduction: Methotrexate (MTX) is a widely used medication that is cleared renally with dose-dependent toxicities affecting multiple organ systems. Renal impairment is associated with delayed serum MTX clearance increasing risks of toxicity. Although lacking a formal definition, delayed clearance typically refers to persistent serum levels exceeding 0.1µmol/L beyond 48-72 hours post-administration.

MTX has been known to sequester in the extravascular space during fluid overload or capillary leak, further compounding toxicity. Since serum measurements reflect only intravascular concentrations, they may underestimate total body burden. As extravascular fluid re-enters circulation, MTX levels rebound despite initial clearance.

Case Description: A 19-year-old healthy male presented with acute abdominal pain, epistaxis, and hematochezia, in the setting of weeks of malaise and fevers. Computerized tomography showed air pockets with thickened terminal ileum, suggestive of perforated appendicitis. Exploratory laparotomy uncovered ischemic colon, ascites, and a cecal mass, resulting in hemicolectomy with ileocolic anastomosis.

After pathology revealed Burkitt lymphoma, COG ANHL1131 protocol was initiated. Over the next several weeks, the patient developed persistent pancytopenia unresponsive to high dose granulocyte colony-stimulating factor (G-CSF), progressive hepatic and renal dysfunction, disseminated fungal and bacterial infections, and diffuse skin desquamation with impaired wound healing.

Upon transfer to our institution, this constellation of symptoms raised suspicion for MTX toxicity, despite lack of renal impairment at the time of MTX administration. Upon further investigation, the patient had significant extravascular fluid collections at the time of MTX administration. Although his serum MTX level was 0.12 µmol/L within 72 hours post-infusion—suggesting appropriate clearance per referring protocol—a delayed rebound to 0.4 µmol/L was observed five weeks later, despite no additional MTX administration.

Once delayed MTX toxicity was confirmed, targeted management was initiated: G-CSF discontinuation, leucovorin rescue, urinary alkalinization, and high-flux hemodialysis. While serum MTX levels initially declined, they rebounded repeatedly, consistent with ongoing redistribution from the extravascular compartment into the intravascular space.

Despite aggressive intervention, the patient’s status deteriorated and he succumbed to overwhelming infection before full MTX clearance could be achieved.

Discussion: Delayed MTX clearance is associated with impaired renal function. However, delayed toxicity due to redistribution from extravascular compartments after apparent serum clearance is likely underrecognized, as monitoring often ceases once levels meet clearance thresholds. This prolonged exposure can result in significant morbidity and mortality.

Standard therapies for MTX toxicity include hydration, urine alkalinization, leucovorin rescue, high-flux hemodialysis, and, in severe cases, glucarpidase, a recombinant carboxypeptidase enzyme that converts MTX into glutamate. Data on glucarpidase use in subacute toxicity remains limited. Methods to assess or eliminate MTX sequestered in extravascular fluid are also poorly defined.

Conclusion: This case underscores the need for continued vigilance for MTX toxicity in volume-overloaded patients with unexplained pancytopenia and organ dysfunction, even after apparent serum clearance. Rebound elevations from extravascular redistribution warrant extended monitoring.