Hispanic ethnicity as a risk factor for requiring glucarpidase rescue in pediatric patients receiving high‐dose methotrexate

Self Cite

Background National drug shortages of essential medications for childhood cancer have increasingly posed a challenge in the treatment of patients. The efficacy of standardized supportive care practices to avoid treatment‐related toxicities may be limited during these drug shortages. High‐dose methotrexate (HDMTX) plays a critical role in modern treatment protocols for acute lymphoblastic leukemia and requires stringent supportive care measures to mitigate toxicity. As the result of a national intravenous (IV) sodium bicarbonate shortage, institutional standard HDMTX supportive care guidelines had to be modified. We describe the unanticipated consequences on HDMTX clearance. Methods We performed a retrospective chart review assessing the impact of alternative compositions of IV fluids on the mean 24‐h methotrexate levels (Cpss) of 25 patients receiving 76 total HDMTX infusions at Texas Children's Hospital Cancer Center from March to October 2017. During the sodium bicarbonate drug shortage, all patients received IV hydration consisting of either dextrose 5%, 0.45% normal saline (D5 ½ NS—Group A) or dextrose 5%, 0.2% normal saline (D5 ¼ NS—Group B). Results Patients receiving a higher total sodium dose demonstrated significantly lower Cpss (25.36 ± 16.6 μMol) compared to patients receiving less sodium (53.9 ± 37.9 μMol; P < .001). Conclusions Our report shows that in the setting of IV sodium bicarbonate shortage, the composition of hydration IV fluids may affect methotrexate clearance. Patient who received a higher sodium load had a lower 24‐h methotrexate level. This demonstrates the potential for unanticipated outcomes resulting from national drug shortages.

Section: Discussioncontrasting

confidence: 44%

“…Group C consists of a historic cohort of 294 patients who received HDMTX at Texas Children's Hospital during the years 2011‐2016, as has been previously described (Table 1). 19 Ten patients had HDMTX infusions in both Groups A and B, with each individual infusion analyzed with its respective group.…”

Section: Resultsmentioning

confidence: 99%

Do intravenous fluid substitutions influence methotrexate clearance? An unanticipated impact of an intravenous sodium bicarbonate drug shortage

Mangum

Bernhardt

Cheng

et al. 2020

Self Cite

“…or Svahn et al. While this difference in proportion may be due to difference in institutional parameters for administration, it was noted that 80% of patients who received CPDG 2 in the TCH study were of self‐reported Hispanic ethnicity, a proportion well over the total proportion of Hispanic patients seen at the Center (35–50% depending on the diagnosis), and a population likely underrepresented in the previous published estimates 11 . Although there appeared to be no difference in 24‐hour MTX serum concentrations between Hispanic and non‐Hispanic patients at the Center, they observed a cluster of Hispanic patients with higher 24‐hour MTX concentrations compared to the other Hispanic and non‐Hispanic patients.…”

Section: Introductionmentioning

confidence: 94%

“…To explain these findings, Schafer et al. hypothesized that MTX‐related pharmacogenomic variants may be more frequent in Hispanic populations and thereby explain the increased rate of CPDG 2 administration in this cluster 11 . There is a growing body of evidence to support the role of genetic ancestry and pharmacogenomic factors in ALL treatment outcomes 12–14 and, more specifically, in MTX toxicity 15–19 .…”

Section: Introductionmentioning

confidence: 99%

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

Zobeck

Bernhardt

Kamdar

et al. 2021

Self Cite

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.

“…9 Although pediatric patients were represented in the published pooled analysis, the analysis population comprised pediatric and adult patients (aged 0−84 years), with most patients (n = 89, 53%) aged 18 years or older. 9 Case series have demonstrated the effectiveness of glucarpidase in pediatric patients, [17][18][19] evaluated risk factors, including Hispanic ethnicity, for pediatric patients requiring glucarpidase use, 20,21 and identified varying levels of awareness of glucarpidase across hematologyoncology centers, demonstrating a need for further information on the use of glucarpidase in pediatric settings. 22 Finally, consensus guidelines on the use of glucarpidase have been published, 8 and the webbased MTXPK.org tool has been developed to help identify patients with delayed MTX elimination, 23 both largely based on the clinical experience in pediatric patients.…”

Section: Introductionmentioning

confidence: 99%

A pooled subgroup analysis of glucarpidase treatment in 86 pediatric, adolescent, and young adult patients receiving high‐dose methotrexate therapy in open‐label trials

Janeway

Gros

Schwartz

et al. 2023

Background Delayed methotrexate elimination can occur in patients undergoing high‐dose methotrexate cancer treatment. Effectiveness of glucarpidase for rapidly reducing methotrexate concentrations was shown in compassionate‐use trials in patients aged 0–84 years. Methods We performed post hoc analyses of infants (≥28 days to <2 years), children (≥2 to <12 years), adolescents (≥12 to <15 years), and young adults (≥15 to <25 years) from four multicenter, open‐label, single‐arm, glucarpidase compassionate‐use trials. Patients had toxic methotrexate levels due to delayed methotrexate elimination and/or renal dysfunction, and received glucarpidase (50 U/kg). The primary endpoint was clinically important reduction (CIR) in plasma methotrexate (methotrexate ≤1 μmol/L at all post‐glucarpidase measurements) based on high‐performance liquid chromatography. Results Among 86 patients included in efficacy analyses, CIR was achieved by zero of one infant (0.0%), five of 16 children (31.3%), seven of 24 adolescents (29.2%), and 26/45 young adults (57.8%). Median methotrexate reduction was 98.7% or higher in each group 15 minutes post‐glucarpidase. Patients with pre‐glucarpidase methotrexate less than 50 μmol/L (35/42, 83.3%) were more likely to achieve CIR than those with methotrexate 50 μmol/L or higher (1/37, 2.7%). The most common treatment‐related adverse event was paresthesia, occurring in three adolescents (4.5%) and six young adults (5.2%). No other treatment‐related adverse event occurred in 5% or higher of any age group. Conclusion After accounting for pre‐glucarpidase methotrexate levels, glucarpidase efficacy at inducing CIR in pediatric/young adult patients was consistent, with efficacy observed in the overall study population (i.e., patients aged 0–84), and no unexpected safety findings were observed. These findings demonstrate glucarpidase (50 U/kg) is an effective and well‐tolerated dose for pediatric, adolescent, and young adult patients.