Neurological Effects During Treatment for ALL Higher in Hispanic Children

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Study results published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) shows that hispanic pediatric patients are more likely than non-Hispanic whites to develop neurotoxicity during the course of methotrexate chemotherapy for acute lymphoblastic lymphoma (ALL).

The study was funded by the National Institutes of Health and the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium.*

Methotrexate (MTX) belongs to the class of chemotherapy drugs called antimetabolites. The drug exerts its chemotherapeutic effect by being able to counteract and compete with folic acid in cancer cells. This results in folic acid deficiency in the cells, which, in turn, causes their death.

Side effects
This action may also effect normal, healthy, cells. This can cause significant side effects in the body, including low white, red and platelet blood cell counts, hair loss, mouth sores, difficulty swallowing, diarrhea, liver, lung, nerve and kidney damage.

These complications and side effects of high-dose methotrexate can be either prevented or decreased by using leucovorin, which provides a source of folic acid for the body’s cells.

Pediatric cancer
Acute lymphoblastic lymphoma or acute lymphocytic leukemia is the most common form of pediatric cancer. Because of newer and better treatment regimens, cancer survival rates for children with ALL have improved dramatically over the past few decades. As a result, the disease is now often curable, with survival rates of approximately 90%.

“However, children from minority populations have experienced lower survival rates than white children,” explained the study’s lead author, 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.

Treatment-related toxicities
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 the study, Scheurer and colleagues examined neurotoxicity resulting from methotrexate chemotherapy, a key component of treatment for ALL.

Study design
Between 2012 and 2017, the researchers enrolled 280 newly diagnosed ALL patients from three pediatric cancer treatment centers—Texas Children’s, the University of Arizona, and the University of Minnesota.

The principal investigators of the parent study were based at Duke University and Texas Children’s. 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.

Neurotoxicity
The study found that 39 patients, or 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 (adjusted HR, 2.43; 95% CI, 1.06–5.58),

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 found that patients who experienced neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate. Six of the 39 patients, or 15.4%, who experienced neurotoxicity had a relapse of ALL during the study period, compared to 13 of the 241 patients, or 2.1%, who did not have neurotoxicity (P = 0.0038).

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.

Rescue drug
Many patients who experience neurotoxicity are treated with leucovorin, a “rescue drug” that can prevent the side effects of methotrexate. Scheurer said previous research has suggested that leucovorin may also reduce the efficacy of methotrexate, contributing to poorer survival outcomes.

Better understanding
Scheurer noted that 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 said.

“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 explained.

Predicting neurotoxicity
Currently, Scheurer and colleagues are researching whether biomarkers could predict neurotoxicity.

“Biomarkers may someday allow us to identify patients up-front, 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 concluded.

Scheurer said 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.

Reference
Taylor OA, Brown AL, Brackett J, Dreyer ZE, Moore IK, Mitby P, Hooke MC, Hockenberry MJ, Lupo PJ, Scheurer ME. Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients. Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-18-0939


* The REDIAL Consortium includes Texas Children’s Cancer and Hematology Centers and Baylor College of Medicine, Children’s Hospital of San Antonio, Children’s UT Southwestern, Cook Children’s, Texas Tech University Health Sciences Center, Vannie E. Cook Jr. Children’s Cancer and Hematology Clinic, and Children’s Hospital of Orange County.

Last Editorial Review: September 11, 2018

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