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.

• Authors: Mark C Zobeck, M Brooke Bernhardt, Kala Y Kamdar, Karen R Rabin, Philip J Lupo, Michael E Scheurer
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 68 Issue 8 Pg. e29036 (08 2021) ISSN: 1545-5017 [Electronic] United States
• PMID: 33788417 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Wiley Periodicals LLC.

Chemical References

• ABCC4 protein, human
• Multidrug Resistance-Associated Proteins
• Recombinant Proteins
• glucarpidase
• gamma-Glutamyl Hydrolase
• Methotrexate

Topics

• Age Factors
• Bayes Theorem
• Child
• Hispanic or Latino (genetics)
• Humans
• Methotrexate (adverse effects)
• Multidrug Resistance-Associated Proteins (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, ethnology, genetics)
• Recombinant Proteins (therapeutic use)
• Risk Factors
• gamma-Glutamyl Hydrolase (genetics, therapeutic use)