DAMPAned Methotrexate: A Case Report and Review of the Management of Acute Methotrexate Toxicity

Abstract

Rationale:Consensus guidelines on the management of methotrexate-induced nephrotoxicity using glucarpidase (Voraxaze) may be relatively unfamiliar to the nephrology community.Presenting concerns of the patient:A 61-year-old man with intravascular large B-cell lymphoma was admitted for cycle #1 of high-dose methotrexate (HDMTX) following 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. On admission, he was clinically euvolemic and had a creatinine clearance of 98 mL/min. He received standard HDMTX toxicity prophylaxis with volume expansion, urinary alkalinization, and leucovorin rescue.Diagnoses:Despite prophylactic efforts, he developed a severe acute kidney injury, creatinine 63 to 226 µmol/L (2.56 mg/dL), following HDMTX, impaired methotrexate clearance, and neurotoxicity manifested by status epilepticus.Interventions:He was given glucarpidase to convert extracellular methotrexate into its inactive metabolites, glutamate and DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) at 52 hours post-HDMTX. Cross-reactivity between commercial methotrexate immunoassays with DAMPA led to falsely elevated methotrexate concentrations for much longer than expected based on the current guideline (5 days instead of <48 hours). This required ongoing monitoring of methotrexate concentration by mass spectrometry.Outcomes:The patient remained nonoliguric and did not develop acute indications for dialysis. Serum creatinine peaked at 608 µmol/L (6.88 mg/dL) 6 days after HDMTX. He ultimately had a full renal and neurologic recovery.Lessons learned:Glucarpidase is an effective option for nonrenal elimination of methotrexate-induced nephrotoxicity. Timing of methotrexate concentration monitoring to assess for toxicity, how to access the drug, and the need for ongoing monitoring by mass spectrometry beyond the guideline recommendation are highlighted for centers where HDMTX therapy may be used.

Clinical Profile of Acute Methotrexate Toxicity in Rheumatic Diseases: A Series of 15 Cases

“…However, most of this data is extrapolated from the treatment of toxicities resulting from high-dose MTX (>500 mg/m 2 ) used in cancer chemotherapy for malignancies like lymphoma, acute lymphoid leukaemia, osteosarcoma, etc. 23,24 Folic acid is supplemented at adequate doses with MTX to prevent toxicity. The FOLVARI trial that compared 10 mg/ week of folic acid to 30 mg/week of folic acid did not report any significant benefits of a higher folate dose, nor were there any risks of supplementing it at a higher dose.…”

“…However, most of this data is extrapolated from the treatment of toxicities resulting from high-dose MTX (>500 mg/m 2 ) used in cancer chemotherapy for malignancies like lymphoma, acute lymphoid leukaemia, osteosarcoma, etc. 23, 24…”

Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy

“…The plasma MTX concentrations for clinical decision-making regarding CPG2 therapy were immediately analyzed at each hospital using a routine assay method. Measurement of the plasma MTX concentrations at each hospital is a commercial immunoassay, and there is a possibility of cross-reactivity between MTX and DAMPA ( 16 ). The same samples were also analyzed at the central laboratory using a quantitative validated analytical method by high-performance liquid chromatography (HPLC) that permits the separation of MTX metabolites such as DAMPA.…”

A Rapid Method for Determination of Serum Methotrexate Using Ultra-High-Performance Liquid Chromatography–Tandem Mass Spectrometry and Its Application in Therapeutic Drug Monitoring

“…This might falsely alarm the clinician which might lead to reconsidering the therapeutic decisions of using MTX. 24 25 Recently, chromatography-based several methods coupled with ultraviolet-visible detector, fluorescence detector, and mass spectrometry (MS) have been introduced to overcome these limitations of immunoassays. Among these methods, liquid chromatography (LC) coupled with tandem MS (LC-MS/MS) has emerged as a potential tool for rapid, sensitive, and cost-effective method for therapeutic drug monitoring of MTX.…”