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.
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: M A H den Hoed; E Lopez-Lopez; M L te Winkel; W Tissing; J D E de Rooij; A Gutierrez-Camino; A Garcia-Orad; E den Boer; R Pieters; S M F Pluijm; R de Jonge; M M van den Heuvel-Eibrink Journal: Pharmacogenomics J Date: 2014-11-04 Impact factor: 3.550
Authors: Jun J Yang; Cheng Cheng; Meenakshi Devidas; Xueyuan Cao; Yiping Fan; Dario Campana; Wenjian Yang; Geoff Neale; Nancy J Cox; Paul Scheet; Michael J Borowitz; Naomi J Winick; Paul L Martin; Cheryl L Willman; W Paul Bowman; Bruce M Camitta; Andrew Carroll; Gregory H Reaman; William L Carroll; Mignon Loh; Stephen P Hunger; Ching-Hon Pui; William E Evans; Mary V Relling Journal: Nat Genet Date: 2011-02-06 Impact factor: 38.330
Authors: Virginia Perez-Andreu; Kathryn G Roberts; Richard C Harvey; Wenjian Yang; Cheng Cheng; Deqing Pei; Heng Xu; Julie Gastier-Foster; Shuyu E; Joshua Yew-Suang Lim; I-Ming Chen; Yiping Fan; Meenakshi Devidas; Michael J Borowitz; Colton Smith; Geoffrey Neale; Esteban G Burchard; Dara G Torgerson; Federico Antillon Klussmann; Cesar Rolando Najera Villagran; Naomi J Winick; Bruce M Camitta; Elizabeth Raetz; Brent Wood; Feng Yue; William L Carroll; Eric Larsen; W Paul Bowman; Mignon L Loh; Michael Dean; Deepa Bhojwani; Ching-Hon Pui; William E Evans; Mary V Relling; Stephen P Hunger; Cheryl L Willman; Charles G Mullighan; Jun J Yang Journal: Nat Genet Date: 2013-10-20 Impact factor: 38.330
Authors: W E Evans; W R Crom; M Abromowitch; R Dodge; A T Look; W P Bowman; S L George; C H Pui Journal: N Engl J Med Date: 1986-02-20 Impact factor: 91.245
Authors: Katalin Csordas; Marta Hegyi; Oliver T Eipel; Judit Muller; Daniel J Erdelyi; Gabor T Kovacs Journal: Anticancer Drugs Date: 2013-02 Impact factor: 2.248
Authors: Geetha Chittoor; Karin Haack; Nitesh R Mehta; Sandra Laston; Shelley A Cole; Anthony G Comuzzie; Nancy F Butte; V Saroja Voruganti Journal: BMC Med Genet Date: 2017-01-17 Impact factor: 2.103
Authors: Laura B Ramsey; Frank M Balis; Maureen M O'Brien; Kjeld Schmiegelow; Jennifer L Pauley; Archie Bleyer; Brigitte C Widemann; David Askenazi; Sharon Bergeron; Anushree Shirali; Stefan Schwartz; Alexander A Vinks; Jesper Heldrup Journal: Oncologist Date: 2017-10-27