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

Abstract

Background: 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.

Procedure: 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.

Results: 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%.

Conclusion: 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.

Keywords: Hispanic ethnicity; ancestry; genetics; glucarpidase; methotrexate; pediatric acute lymphoblastic leukemia.

FIGURE 1

Results of logistic regression models for the association of each SNV and CPDG₂ requirement. Each estimate is controlled for genetic ancestry and estimates are reported on the log-odds scale. All estimates are transformed to represent positive associations (i.e the allele associated with increased risk for CPDG₂ is the “risk” allele). Light blue points represent median values. Thick navy lines represent 50% compatibility intervals. Thin light blue lines represent 95% compatibility intervals.