Researchers have identified certain novel risk factors for requiring glucarpidase rescue associated with high-dose methotrexate, including Hispanic ethnicity.

In a single-center study, researchers reviewed cases of 423 patients with acute lymphoblastic leukemia (ALL) treated with methotrexate between 1000 and 5000 mg/m2 from 2010 to 2017 and compared characteristics of those who received glucarpidase with those who did not.

Of the 423 cases, 18 received glucarpidase; 94% of these patients were Hispanic. No patient who received a lower dose of methotrexate (1000 or 2000 mg/m2) received glucarpidase. The median age of patients who received glucarpidase was 12.7 years.

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Multivariable analysis showed that self-reported Hispanic ethnicity was associated with an almost 5 times greater risk of requiring glucarpidase (odds ratio [OR]=4.68; 95% CI, 1.63-15.06). According to the researchers, Hispanic ethnicity previously has been implicated in the risk of methotrexate toxicity and poor ALL treatment outcomes.

In addition, older age was associated with an increased likelihood of requiring glucarpidase (OR=1.87; 95% CI, 1.17-3.17).

“Our model reported an 80% increase in the odds of relapse for every 5-year increase in age,” the researchers reported.

The researchers also conducted genomic analysis of 177 patients, of whom 11 received glucarpidase. They found that each additional G allele of rs7317112 in ABCC4 increased the odds of requiring glucarpidase. Six other loci demonstrated probabilities of association with receipt of glucarpidase (NTRK1/rs10908521, TSG1/rs9345389, STT3B/rs1353327, SCLO1B1/rs4149056, GATA3/rs3824662, and ARID5B/rs10821936).

The researchers noted that a limitation of the study was the small number of events in the dataset; however, they concluded that “These findings give clinicians important information to better estimate the risk for requiring [glucarpidase] in their patients.”


Zobeck MC, Bernhardt MB, Kamdar KY, et al.  Pediatr Blood Cancer. Published online March 31, 2021. doi:10.1002/pbc.29036