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Administration of high-dose methotrexate (HDMTX) is a component of many chemotherapy regimens in lymphoma and acute lymphoblastic leukemia. HDMTX is administered in the hospital so that patients may be closely monitored with administration of sodium bicarbonate, urine output, and pH analysis, as well as monitoring for acute kidney injury (AKI).

While administration of HDMTX is routine and generally well tolerated, complications can be severe and life-threatening. These include not only AKI but also liver failure, neurologic toxicity, mucositis, severe neutropenia, and infections. Thankfully, the latter complications are rare, but AKI has been reported to occur in ~10% of patients with lymphoma.

In the study by, the investigators performed a retrospective analysis of electronic medical records at the Mayo Clinic in Rochester, Minnesota to assess for risk factors associated with AKI after HDMTX. Included were lymphoma patients treated with HDMTX from January 1, 2002 to December 31, 2018 and identified 642 patients treated with a total of 2,804 cycles of HDMTX.

Surprisingly, the rate of AKI was 19% amongst this population -- nearly double what was previously reported. The authors do not give a reason for the higher rate observed in this study, but it could be due to the older age of the cohort (median 66 years) as well as high body mass index (BMI, median 26.4) and body surface area (BSA, median 1.97).

A multivariate analysis for risk of AKI grade 2 or higher identified older age, male sex, and higher BSA as patient-specific factors associated with higher risk. Higher doses of methotrexate, first cycle administration and a 48-hour methotrexate serum level greater than 1.28 were also associated with increased rates of AKI.

The authors conclude that this threshold level (1.28 at 48 hours) was also associated with greater length of hospital stay, intensive care unit admission, and 30-day mortality.

While this retrospective study did not assess for potential interventions and the generalizability may be affected by the racial homogeneity of the population, it provides knowledge of risk factors that should be considered before prescribing HDMTX if there are other alternatives and a 48-hour threshold level that should increase concern for potential complications.

Justin Taylor, MD, is assistant professor in the Division of Hematology and a member of the Cancer Epigenetics Program at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine.

Read the study here and an interview about it here.