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Hispanic pediatric patients were more likely than non-Hispanic whites to develop neurotoxicity during the course of methotrexate chemotherapy for acute lymphoblastic lymphoma (ALL). For many patients, the symptoms prompted modifications to their treatment regimens, potentially raising the risk of relapse.

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Due to improvements in treatment regimens over the past few decades, ALL is now often curable, with survival rates of approximately 90 percent. However, children from minority populations have experienced lower survival rates than white children.


Previous research has indicated that minority populations may experience higher rates of treatment-related toxicities, which can result in modifications to a patient's treatment plan. In this study, Michael E. Scheurer, PhD, MPH, Associate Professor of Pediatrics at Baylor College of Medicine and Director of the Epidemiology Center at Texas Children's Cancer Center, Houston, and colleagues examined neurotoxicity resulting from methotrexate chemotherapy (Clin Cancer Res 2018; doi:10.1158/1078-0432.CCR-18-0939).


Study Details

Between 2012 and 2017, the researchers enrolled 280 newly diagnosed ALL patients from three pediatric cancer treatment centers-Duke University, the University of Arizona, and the University of Minnesota. They examined medical records for suspected cases of neurotoxicity, which may present as altered mental status, seizures, or stroke-like symptoms. They used Cox proportional hazards to estimate the association between race/ethnicity and methotrexate neurotoxicity.


The study found that 39 patients (13.9%) experienced neurotoxicity. Hispanic patients experienced neurotoxicity more than twice as often as non-Hispanic whites, after controlling for sex, age at diagnosis, body mass index, and ALL risk stratification. Nine of the 39 patients experienced a second neurotoxic event; all nine of these patients were Hispanic. Other racial/ethnic groups, including non-Hispanic black, were included in the study, but the population was too small to draw conclusions in these populations.


Furthermore, the study discovered that patients who experienced neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate. Six of the 39 patients (15.4%), who experienced neurotoxicity had a relapse of ALL, compared to 13 of the 241 patients (2.1%), who did not have neurotoxicity.


Scheurer noted the study's primary limitation is there has not yet been sufficient follow-up time to examine the long-term effects of neurotoxicity. Also, larger studies with more representation of non-Hispanic black and Asian patients will further contribute to understanding of this issue.



Scheurer explained that when a patient experiences a neurotoxic event, physicians will review the patient's treatment and may reduce the number of planned doses or suspend treatment. Many patients who experience neurotoxicity are treated with leucovorin, a "rescue drug" that can prevent the side effects of methotrexate. He noted previous research has suggested that leucovorin may also reduce the efficacy of methotrexate, contributing to poorer survival outcomes.


According to Scheurer, further research is required to understand why Hispanic children are more likely than whites to experience treatment-altering neurotoxicity. However, this study contributes to a greater understanding of survival disparities in ALL.


"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," Scheurer continued. "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."


Currently, the researchers are focusing on whether biomarkers could predict neurotoxicity.


"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," Scheurer explained.