Novel risk factors for glucarpidase use in pediatric acute lymphoblastic leukemia: Hispanic ethnicity, age, and the ABCC4 gene.

BACKGROUND

Carboxypeptidase G (CPDG ; 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 CDPG , we evaluated the role of demographic, clinical, and genetic factors for CPDG use.

PROCEDURE

Cases who received CPDG 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/m between 2010 and 2017. We used multivariable Bayesian logistic regression to evaluate the association of CPDG 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.

RESULTS

We identified 423 patients who received 1592 doses of MTX. Of the 18 patients who received CPDG , 17 (94%) were Hispanic. No patients who received 1000 or 2000 mg/m of MTX received CPDG . 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 CPDG . Of the 177 patients in the genomic cohort, 11 received CPDG . Each additional G allele of rs7317112 in ABCC4 increased the odds of requiring CPDG (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%.

CONCLUSION

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