Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance

Abstract

Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36-hour concentration is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is above 5 µM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase may be indicated. After a 36- to 42-hour HDMTX infusion, glucarpidase may be indicated when the 48-hour methotrexate concentration is above 5 µM. Administration of glucarpidase should optimally occur within 48-60 hours from the start of the HDMTX infusion, because life-threatening toxicities may not be preventable beyond this time point.

Implications for practice: Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication on the label does not give specific methotrexate concentrations above which it should be used. An international group of experts was convened to develop a consensus guideline that was specific and evidence-based to identify the population of patients who would benefit from glucarpidase.

Keywords: Acute kidney injury; Creatinine; Glucarpidase; Leucovorin; Methotrexate.

Figure 1.

The cellular entry of MTX is mediated primarily by the ubiquitously expressed RFC, encoded by the human solute carrier family 19 member 1 (SLC19A1) gene on chromosome 21. Other influx and efflux mechanisms include ABC transporters (specifically ABCC1–4) and breast cancer resistance protein [79], but their role in MTX clearance and efficacy is less well documented. Passive diffusion plays a significant role during high‐dose MTX (HDMTX) therapy. Most of the MTX that enters the liver re‐enters the blood circulation by enterohepatic circulation via the ABCC transporters, and only a small portion is excreted into the bile. MTX interferes with the natural folate‐homocysteine cycle and inhibits folate‐dependent enzymes and pathways, including DHFR, TYMS, 5,10‐methylene‐tetrahydrofolate reductase, and purine de novo synthesis. This leads to a lack of reduced folate, inhibition of DNA synthesis, increased homocysteine and adenosine concentrations, and potentially life‐threatening toxicities [32], [80], [81]. Leucovorin (folinic acid) is essential for cellular rescue after HDMTX, and insufficient intracellular concentrations of leucovorin after HDMTX may cause life‐threatening toxicities. Intracellularly, the enzyme FPGS polyglutamates MTX by adding 2–6 glutamate residues, creating MTXPG, which increases intracellular retention as well as affinity for its target enzymes proportional to glutamyl chain lengths [82], [83], [84], [85], [86]. Abbreviations: 5‐FP, 5‐formylpteroate; ABC, ATP‐binding cassette; ABCC, ABC subfamily C; CH₂THF, 5,10‐Methylenetetrahydrofolate; DAMPA, 4‐deoxy‐4‐amino‐N10‐methylpteroic acid; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FPGS, folylpolyglutamate synthetase; GLU, glutamate; LV, leucovorin, MTX, methotrexate; MTXPG, polyglutamated methotrexate; RFC, reduced folate carrier; SHMT1, serine hydroxymethyltransferase 1; THF, tetrahydrofolate; TYMS, thymidylate synthase.

Figure 2.

Change in serum creatinine (A) and plasma methotrexate (B) concentrations relative to the start of the high‐dose methotrexate infusion (time 0) in pediatric patients with acute lymphoblastic leukemia (ALL) receiving 5 g/m² over 24 hours on the Nordic Society of Paediatric Haematology and Oncology ALL‐2008 protocol who also received GP. Their measurements prior to glucarpidase (blue) and after glucarpidase (green) are shown relative to the predicted mean and 95% CI for patients receiving the same MTX dose (orange lines). Abbreviations: CI, confidence interval; GP, glucarpidase; HPLC, high pressure liquid chromatography; MTX, methotrexate.

Figure 3.

Methotrexate is cleaved into two noncytotoxic metabolites, DAMPA and glutamic acid, by CPDG₂. Abbreviations: CPDG₂, glucarpidase; DAMPA, 4‐deoxy‐4‐amino‐N10‐methylpteroic acid.

Figure 4.

Concentrations of MTX and SCr in a patient enrolled on the Nordic Society of Paediatric Haematology and Oncology acute lymphoblastic leukemia 2008 protocol treated with glucarpidase following a 5 g/m² dose of MTX over 24 hours. The HPLC measurement of MTX (blue line) is more accurate than the FPIA measurement of MTX (green line) for the 48 hours following the administration of glucarpidase at hour 41. The HPLC measurement shows a rebound of the MTX concentrations from hour 60 to hour 96. The SCr increased during the 24‐hour infusion and remained high for several days following the glucarpidase administration. The FPIA and HPLC measurements were performed by Stein Bergan at the Department of Pharmacology, Rikshospitalet, Oslo, Norway. Abbreviations: conc, concentration; FPIA, fluorescence polarization immunoassay; HPLC, high pressure liquid chromatography; MTX, methotrexate; SCr, serum creatinine.

Figure 5.

Treatment with glucarpidase may be indicated in the case of excessively high MTX concentrations and rising creatinine. Time points indicated are after the start of the infusion and are not required measurement times. Guidance is provided for time points that are routinely measured in clinical practice. Renal toxicity grade 3+ is according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4. Concentrations in µM can be converted to µg/mL by dividing by 2.2005. 120 µM = 54.5 µg/mL, 50 µM = 22.7 µg/mL, 30 µM = 13.6 µg/mL, 10 µM = 4.54 µg/mL, and 5 µM = 2.27 µg/mL. *Urine pH >7, urine output >2.5L/m² per day, emesis control. ^†Hours are indicated after infusion start. Abbreviations: Cr, serum creatinine; GFR, glomerular filtration rate; HDMTX, high‐dose methotrexate; LV, leucovorin (folinic acid, citrovorum factor, 5‐methyltetrahydrofolate); MTX, methotrexate; [MTX], plasma methotrexate concentration.

Figure 6.

Standard leucovorin nomogram used in the U.S. Glucarpidase use may be indicated when MTX concentrations are within the shaded area. Abbreviation: MTX, methotrexate.