Study Finds Hispanic Pediatric Patients at Increased Risk of Methotrexate Neurotoxicity During Treatment for ALL
Case studies have reported a high prevalence of methotrexate subacute neurotoxicity among Hispanic adolescents with acute lymphoblastic leukemia (ALL), suggesting sensitivity to methotrexate therapy may differ by race and ethnicity. Now, a prospective study in pediatric patients with ALL has found that Hispanic ethnicity was linked with an increased risk of developing methotrexate neurotoxicity, which was, in turn, associated with treatment modifications and disease relapse. Future studies are needed to evaluate biologic factors that may modify the risk of neurotoxicity among vulnerable patients, including Hispanic children with ALL. The study was published by Taylor et al in Clinical Cancer Research.
Study Methodology
Between 2012 and 2017, the researchers enrolled 280 newly diagnosed patients with ALL into a prospective study of treatment-related toxicity. The patients were undergoing treatment at one of three major pediatric cancer treatment centers in the United States, including the University of Arizona in Tucson, Children’s Minnesota in Minneapolis, and Texas Children’s Cancer Center in Houston.
The researchers reviewed the patients’ electronic medical records for suspected cases of acute or subacute methotrexate neurotoxicity. Suspected cases were defined as patients with a neurologic event, including stroke-like symptoms, aphasia, and seizures following intrathecal and/or intravenous methotrexate that resulted in modifications in intrathecal and/or intravenous methotrexate therapy.
Demographic information—such as patients’ sex, race, and ethnicity, and clinical information, such as diagnosis, chemotherapy dose, treatment risk group assignment, minimal residual disease status at day 29 of therapy, height and weight at diagnosis, and date of relapse or death—were also abstracted from the patients’ electronic medical records for review. Cox proportional hazards models were used to estimate the association between race/ethnicity and methotrexate neurotoxicity. Multivariable linear regression models compared treatment outcomes between patients with and without methotrexate neurotoxicity.
Study Results
The researchers found that of the 280 newly diagnosed patients enrolled in the study, 39 (13.9%) experienced methotrexate neurotoxicity. Compared with non-Hispanic whites, Hispanic patients experienced the greatest risk of methotrexate neurotoxicity (adjusted hazard ratio [HR] = 2.43, 95% confidence interval [CI] = 1.06–5.58) after accounting for sex, age at diagnosis, body mass index Z-score at diagnosis, and ALL risk stratification.
Patients who experienced a neurotoxic event received an average of 2.25 fewer doses of intrathecal methotrexate. Of the 39 cases of neurotoxicity, 6 (15.4%) experienced relapse during the study period, compared with 13 (2.1%) of the 241 patients without methotrexate neurotoxicity (P = .0038).
“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” said Michael E. Scheurer, PhD, MPH, Associate Professor of Pediatrics at Baylor College of Medicine, Director of the Epidemiology Center at Texas Children’s Cancer Center, and a coauthor of the study.
“We want to make sure that we maintain the benefit of therapy for ALL, while trying to reduce disparities and minimize any of the risks,” he continued. “Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes. If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”
Funding for the study was provided by the National Institutes of Health and the Reducing Ethnic Disparities in Acute Leukemia Consortium. The study authors reported no conflicts of interest.
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