Preventing and Managing Toxicities of High-Dose Methotrexate

Abstract

: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m², is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.

Implications for practice: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m², is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.

Keywords: Acute kidney injury; Glucarpidase; High-dose methotrexate; Leucovorin; Methotrexate; Pharmacokinetics.

Figure 1.

Mechanism and site of action of MTX and of rescue strategies for delayed MTX elimination. After MTX enters cells through the RFC, it is polyglutamated, then competitively and reversibly inhibits the activity of DHFR, thus preventing formation of FH₄ from FH₂. The lack of FH₄ inhibits DNA, RNA, and protein synthesis. LV enters cells through the RFC and allows formation of FH₄ despite the presence of MTX, which effectively rescues cells. However, when MTX elimination is impaired and it is present at very high concentrations, very high doses of LV are necessary to allow entry of a sufficient amount to rescue cells from MTX toxicity. Glucarpidase eliminates extracellular MTX by converting it to nontoxic DAMPA and therefore should always be given with LV to provide intracellular rescue even as the glucarpidase prevents further accumulation of intracellular MTX by removing it from the extracellular compartment. Abbreviations: DAMPA, 4-deoxy-4-amino-N-10-methylpteroic acid; DHFR, dihydrofolate reductase; dUMP, deoxyuridine monophosphate; FH₂, dihydrofolate; FH₄, tetrahydrofolate; FH₅, tetrahydrofolate; LV, leucovorin; MTX, methotrexate; RFC, reduced folate carrier; TMP, thymidine monophosphate.

Figure 2.

Nomogram for the expected time-dependent decrease in serum MTX levels after completion of MTX infusion. Nomogram for expected serum MTX levels as a function of time from the end of a 6-hour infusion of methotrexate at a dose of 7.5 g/m². The dark blue area represents ±2 SD from the mean (orange line). Values above the red line indicate impending or severe toxicity. Adapted from [112] with permission. Abbreviation: MTX, methotrexate.

Figure 3.

Pharmacokinetically guided leucovorin rescue based on plasma MTX levels after high-dose MTX. Leucovorin dosing must be increased dramatically when plasma MTX levels are elevated above 5 µM at 42 hours after the start of the MTX infusion because leucovorin must compete with MTX to enter cells via the reduced folate carrier and the goal of leucovorin rescue is to achieve a high intracellular concentration of leucovorin. In color are the recommended doses of leucovorin based on the plasma MTX concentration at each time point after the start of the MTX infusion. For example, if at hour 60 the MTX concentration is 100 µM, it falls above the red line and the recommended leucovorin dose would be 1,000 mg/m² every 6 hours. If at 100 hours the methotrexate concentration decreases to 3 µM (above the yellow line, below the orange line), then the recommended leucovorin dose would decrease to 10 mg/m² every 3 hours. The dotted lines indicate extrapolated values based on modeling and clinical trial experience following the original publication [113]. Abbreviation: MTX, methotrexate.