Ethnic-specific predictors of neurotoxicity among patients with pediatric acute lymphoblastic leukemia after high-dose methotrexate.

BACKGROUND: High-dose methotrexate (HD-MTX; 5000 mg/m2 ) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity, which may disproportionately affect Latino children. This study evaluated risk factors for neurotoxicity after HD-MTX in an ethnically diverse population of patients with ALL. METHODS: The authors retrospectively reviewed the medical records of patients who were diagnosed with ALL and treated with HD-MTX at Texas Children's Cancer Center (2010-2017). Methotrexate neurotoxicity was defined as a neurologic episode (e.g., seizures or stroke-like symptoms) occurring within 21 days of HD-MTX that resulted in methotrexate treatment modifications. Mixed effects multivariable logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between clinical factors and neurotoxicity. RESULTS: Overall, 351 patients (58.1% Latino) who received 1183 HD-MTX infusions were evaluated. Thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, the authors observed that serum creatinine elevations ≥50% of baseline were associated with a three-fold increased odds (OR, 3.32; 95% CI, 0.98-11.21; p = .05) for neurotoxicity compared with creatinine elevation <25%. Notably, predictors of neurotoxicity differed by ethnicity. Specifically, Latino children experienced a nearly six-fold increase in neurotoxicity odds (OR, 5.80; 95% CI, 1.39-24.17; p = .02) with serum creatinine elevation ≥50% compared with creatinine elevation <25%. CONCLUSIONS: The current findings indicate that serum creatinine elevations ≥50% may be associated with an increased risk for neurotoxicity among Latino children with ALL and may identify potential candidates for therapeutic or supportive care interventions.

Ripple mapping: A precise tool for atrioventricular nodal reentrant tachycardia ablation.

INTRODUCTION: Ablation for atrioventricular nodal reentrant tachycardia (AVNRT) classically utilizes evaluation of signal morphology within the anatomic region of the slow pathway (SP), which involves subjectivity. Ripple mapping (RM; CARTO-3© Biosense Webster Inc) displays each electrogram at its three-dimensional coordinate as a bar changing in length according to its voltage-time relationship. This allows prolonged, low-amplitude signals to be displayed in their entirety, helping identify propagation in low-voltage areas. We set out to evaluate the ability of RM to locate the anatomic site of the SP and assess its use in guiding ablation for AVNRT. METHODS: Patients ≤18 years with AVNRT in the EP laboratory between 2017 and 2021 were evaluated. RM was performed to define region of SP conduction in patients from 2019 to 2021, whereas standard electro-anatomical mapping was used from 2017 to 2019. All ablations were performed using cryotherapy. Demographics, outcomes, and analysis of variance in number of test lesions until success was compared between groups. RESULTS: A total of 115 patients underwent AVRNT ablation during the study; 46 patients were in the RM group and 69 were in the control group. There were no demographic differences between groups. All procedures, in both groups, were acutely successful. In RM group, 89% of first successful lesions were within 4 mm of the predicted site. There was significantly reduced variability in number of test lesions until success in the RM group (p = .01). CONCLUSION: RM is a novel technique that can help identify SP location, allowing for successful ablation of AVNRT with decreased variability.

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

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.