Novel risk factors for glucarpidase use in pediatric acute lymphoblastic leukemia: Hispanic ethnicity, age, and the...

Carboxypeptidase G₂ (CPDG₂ ; glucarpidase) is a rescue drug for patients at risk for kidney injury from high-dose methotrexate (MTX). As there are no strategies for predicting patients who will require CDPG₂ , we evaluated the role of demographic, clinical, and genetic factors for CPDG₂ use.

Cases who received CPDG₂ and controls who did not were identified by chart review of acute lymphoblastic leukemia (ALL) patients who received MTX doses between 1000 and 5000 mg/m² between 2010 and 2017. We used multivariable Bayesian logistic regression to evaluate the association of CPDG₂ use with demographic and clinical variables and, on a subset of patients, with genetic ancestry and 49 single nucleotide variants previously associated with MTX toxicity.

We identified 423 patients who received 1592 doses of MTX. Of the 18 patients who received CPDG₂ , 17 (94%) were Hispanic. No patients who received 1000 or 2000 mg/m² of MTX received CPDG₂ . Hispanic ethnicity (odds ratio: 4.68; 95% compatibility interval: 1.63-15.06) and older age (1.87 [1.17-3.17]) were associated with receiving CPDG₂ . Of the 177 patients in the genomic cohort, 11 received CPDG₂ . Each additional G allele of rs7317112 in ABCC4 increased the odds of requiring CPDG₂ (3.10 [1.12-6.75]). Six other loci (NTRK1/rs10908521, TSG1/rs9345389, STT3B/rs1353327, SCLO1B1/rs4149056, GATA3/rs3824662, ARID5B/rs10821936) demonstrated probabilities of association between 88% and 97%.

We demonstrated that demographic characteristics, including Hispanic ethnicity and age, are associated with CPDG₂ use. Additionally, we provide evidence that inherited genetic variation is associated with risk of requiring CPDG₂ . If validated in independent populations, this information could be leveraged to develop targeted toxicity prevention strategies for children with ALL.