Hispanic ethnicity as a risk factor for requiring glucarpidase rescue in pediatric patients receiving high‐dose methotrexate
Authors: Eric S. Schafer, M. Brooke Bernhardt, Kate E. Reichert, Tara E. Haworth, Mona D. Shah
Journal: American Journal of Hematology (2017)

Even in the era of precision and targeted therapies for neoplastic disorders, high dose methotrexate (HDMTX)—defined as >1 g/m2—remains a staple for the treatment of many hematologic, systemic solid and central nervous system tumors. While lower doses of methotrexate are typically well tolerated, HDMTX requires aggressive supportive care to reduce the risk of drug-related toxicities.1 Despite supportive care measures, HDMTX may cause significant toxicity including mucositis, myelosuppression, central nervous system injury, hepatic injury, acute kidney injury (AKI), and even death in 2–12% of patients.2 Life-threatening methotrexate-induced toxicities have historically been treated with various modalities of dialysis, but after its initial testing in human subjects in the 1990s, an alternative to dialysis: the drug glucarpidase (Voraxaze®), a carboxypeptidase G2 (GPDG2) enzyme analog, which inactivates methotrexate by hydrolyzing the terminal glutamate from naturally occurring folate analogs became a highly effective but expensive alternative.1 Potential risk factors for delayed methotrexate clearance and subsequent toxicities include renal injury prior to the HDMTX infusion, low urine pH, and emesis occurring during the infusion.3 However, other than overt renal insufficiency, host risk factors predicting the need for glucarpidase use have been difficult to identify. Several excellent and large-scale retrospective reviews of glucarpidase use in pediatric oncology patients have been unable to identify additional risk factors for delayed clearance of HDMTX.4-6 However, these studies did note that between 1.8 to 3.6% of patients receiving HDMTX required glucarpidase.4-6 A recent high-level review of data at our institution indicated that our glucarpidase use was substantially higher than the published incidence rates. We therefore, conducted a retrospective cohort study of children and adolescents (ages 0 to 25 years) evaluated for oncologic disease at the Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine (Houston, TX) attempting to identify institution- and patient-specific characteristics which may increase the rate of HDMTX toxicity and subsequently increased our glucarpidase utilization. Based on availability of data, we performed an intensive analysis of patients with acute lymphoblastic leukemia (ALL) who received HDMTX (including those who required glucarpidase) between January 1, 2011 and December 31, 2016 and a disease and demographic review of all patients who received glucarpidase from June 1, 2002 and December 31, 2016. Full methods are described in the supplement. Descriptive statistics were used to summarize demographic details. Discrete data were analyzed using STATA SE v15 (StataCorp LLC, College Station, TX). Nonparametric distributions of data were assumed and therefore, median and ranges were calculated and comparative analyses were performed using Pearson's chi-square, Wilcoxon rank sum and Kruskal-Wallis equality-of-populations rank tests. The review of glucarpidase use in patients with ALL (Table 1) at our institution over the last 6 years (2011–2016) demonstrated a utilization rate (6.1% (18/294) of patients receiving HDMTX, 1.7% (18/1,054) of courses/administrations of HDMTX) substantially higher than any previous epidemiological report.4, 6 When we explored potential high rates of known risk factors of delayed methotrexate clearance, such as poor urine alkalization, poor systemic hydration, contemporaneous or history of poor renal function or high grade nausea/vomiting/anorexia,3 we found no explanation for our Centers' high glucarpidase utilization (Supporting Information Tables S1-S4). However, we found that 93.4% of the patients were self-identified Hispanic ethnicity (Table 1). When compared with the demographics of all patients with ALL who received HDMTX over that period (55.4% of whom were Hispanic, Supporting Information Table S5), the Hispanic predominance was unexpected and statistically significant (P = 0.002). When we identified all patients at our Centers who, between June 1, 2002 and December 31, 2016, received glucarpidase with any disease (Table 1), we noted that 29 of 36 patients (80.6%) were self-identified Hispanic. This is essentially double the rate of Hispanic population of both our Centers (35–50% over the last 5 years) and our Centers' largest catchment area, Harris County, TX (42.4% in 2016 [https://www.census.gov/quickfacts/fact/table/harriscountytexas/PST045216]). Therefore, we believe that our high glucarpidase utilization can be explained by the fact that Hispanic patients have a higher risk of poor methotrexate clearance and that this phenomenon became clinically observable here because of our Centers' substantial Hispanic population. ALL only (2011–2016) n = 18 Entire cohort (2002–2016) n = 36 While admittedly, correlation does not correspond to causation, our findings are notable. When we explored the possibility that Hispanic patients simply have global deficiencies in methotrexate clearance, we found Hispanic patients do not have a lower clearance than do other ethnic groups (Supporting Information Table S6). This finding suggests that the phenomenon we have identified (i.e., delayed clearance of HDMTX in Hispanic patients) is not an issue with ethnicity per se but perhaps a pharmacogenomic phenomenon which is clustered in Hispanics. A boxplot of end-24-h (end-infusion/steady state) methotrexate concentrations (Cpss) for all ALL patients who received HDMTX in the 2011–2016 subcohort seems to visually corroborate this idea as we noticed an intriguing subclustering of outlying patients in the Hispanic cohort not seen in the other groups (Supporting Information Figure S1). Our study has several important limitations most of which are intrinsic to the study design being a single-institution retrospective cohort analysis and are discussed in detail in the supplement. While there have been reports of glucarpidase use in children,4, 6 none have presented data as pertains to race and ethnicity. Therefore, not only is this the first report of Hispanic ethnicity as a possible risk factor for delayed methotrexate clearance and glucarpidase use, but it is the first large scale report of any race and ethnicity characteristics in glucarpidase patients. The inter- and intrapatient variability of methotrexate has puzzled clinicians and investigators for decades. Based on our findings, we believe that at least some of the variability experienced may be influenced by ethnicity, making Hispanic ethnicity—or at least a biological phenomenon clustered within Hispanic patients—a potential new risk factor for delayed methotrexate clearance, necessitating glucarpidase use—and one that deserves further investigation. This work was partially funded by the Killian Owen Curing Kids Cancer Fellowship in Developmental Therapeutics (ESS). The authors report no disclosures or conflicts of interest as it pertains to this manuscript. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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