Methotrexate is frequently used in the treatment of hematological malignancies with central nervous system (CNS) involvement because it can penetrate the blood-brain barrier when administered in doses of 1 g/m2 or more. However, it does carry a toxicity risk that requires some preemptive mitigation strategies — and sometimes those prophylactic strategies are enough to ward off the toxicities.

A team of researchers set out to determine whether certain risk factors for the nephrotoxicity associated with intravenous methotrexate could be modified and published their findings in Leukemia & Lymphoma.

The retrospective analysis included 144 patients in three Australian health care facilities with a total of 539 episodes of high-dose methotrexate (HD-MTX), or doses of 1 g/m2 or higher, between 2009 and 2014, and they correlated toxicity with risk factors.

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They found that “clinically relevant nephrotoxicity” occurred in 36 of the episodes, and the only independent risk factors associated with nephrotoxicity were high-dose MTX of 6 g/m2 or more and interacting/nephrotoxic drugs. Meanwhile, doses of methotrexate that fell into the 3 g/m2 to 3.5 g/m2  range were not associated with nephrotoxicity.

The researchers also acknowledged that certain factors such as increasing age and low albumin levels are associated with prolonged clearance (although they do not increase the risk of renal injury). “Importantly, prolonged MTX clearance was not independently correlated with nephrotoxicity,” the authors wrote, adding that their data suggested that hypoalbuminemia shouldn’t be considered a contraindication to high-dose MTX.

The study was limited by its retrospective nature of “real-world patients,” making the confounders for the toxicities “unavoidable.” The researchers noted that patients who had more severe renal dysfunction at baseline were excluded from receiving high-dose methotrexate, making it more difficult to “determine the effect of baseline renal dysfunction on toxicity and clearance.” Also, the researchers did not have access to MTHFR gene test results, which may have provided useful info on increased risk for methotrexate-related toxicity.

“We have demonstrated in a cohort of patients with minimal baseline rental dysfunction that dose ≥6 g/m2 and interacting/nephrotoxic drugs increased the risk of both prolonged MTX clearance and nephrotoxicity,” the researchers concluded. “In the absence of these, nephrotoxicity was very uncommon, suggesting that modifying these risk factors allows the safe and tolerable delivery of this important chemotherapeutic agent in the vast majority of selected patients.”


Wight J, Ku M, Garwood M, et al. Toxicity associated with high-dose intravenous methotrexate for hematological malignancies. Leuk Lymphoma. Published online May 16, 2022. doi:10.1080/10428194.2022.2074987