Double the Risk for Neurotoxicity for Hispanic Kids From ALL Rx

Pam Harrison

September 12, 2018

Hispanic children who have acute lymphoblastic leukemia (ALL) are more susceptible to developing methotrexate-induced neurotoxicity than non-Hispanic children during the course of a standard ALL treatment protocol, new research indicates.

In a cohort of 280 children of various ethnicities who had ALL and who were seen at clinics in Arizona, Minnesota, and Texas, 39 children developed neurotoxicity; of that group, nearly three quarters (n = 29; 74.4%) were Hispanic. This was a considerably higher proportion than whites (n = 8; 20.5%) and blacks (n = 2; 5.1%), the study authors note.

Using Cox proportional hazards models, the researchers report that, compared to white children, Hispanic children were almost 2.5 times more likely to develop neurotoxicity after adjusting for sex, age at diagnosis, body mass index (BMI) Z-score, and ALL risk stratification (adjusted hazard ratio [HR], 2.43).

As a consequence of this neurotoxicity, these children are more likely to receive significantly fewer doses of intrathecal methotrexate and slightly lower cumulative doses of intravenous (IV) methotrexate than children who do not develop neurotoxicity and are thus more likely to relapse, the research shows.

"Methotrexate is a key component of contemporary chemotherapy for acute lymphoblastic leukemia (ALL), the most common malignancy diagnosed among those less than 15 years of age in the United States," writes Olga Taylor, MPH, Baylor College of Medicine and Texas Children's Hospital, Houston, and colleagues.

"These findings add to the growing body of evidence indicating that minority patients, in particular Hispanics, often encounter significant disparities in terms of treatment outcomes for pediatric ALL," they add.

The study was published online September 11 in Clinical Cancer Research.

Neurotoxicity Tied to High- or Very-High-Risk Treatment

The 280 newly diagnosed pediatric patients were enrolled in the study between November 2012 and February 2017. The median age of the group at the time of diagnosis was 8.4 years.

Investigators reviewed electronic medical records to identify cases of acute or subacute neurotoxicity associated with treatment with methotrexate.

Neurotoxic events were defined as strokelike symptoms, aphasia, or seizures following treatment with intrathecal methotrexate, IV methotrexate, or both and that led to a modification in the dose of methotrexate.

Participants were followed from the time they were diagnosed with ALL to the initiation of maintenance or continuation therapy.

During a median follow-up of 22.6 months, 13.9% of the cohort developed either acute or subacute methotrexate neurotoxicity, the study authors report.

"Most cases of neurotoxicity presented with stroke-like symptoms (n = 24), seizures (n = 6), altered mental status (n = 3), or both altered mental status and stroke-like symptoms (n = 2)," Taylor and colleagues elaborate.

Participants who were more susceptible to developing neurotoxicity were significantly older when ALL was diagnosed than those who did not experience neurotoxicity (aged 12.2 years vs 7.8 years).

They were also more likely to have a greater BMI Z-score than those who did not develop neurotoxicity (0.80 vs 0.14), the investigators state.

Importantly, 84.6% of the children who developed neurotoxicity were receiving high- or very-high-risk treatment, compared with 54.2% of children who did not experience neurotoxicity.

Second Event

Furthermore, 23.1% of patients who developed methotrexate neurotoxicity experienced a second neurotoxic event — "all of whom were Hispanic (P = .079)," the authors point out.

When second events occurred, they were similar in nature to the first event, they note.

"Independent of treatment risk arm, sex, BMI Z-score at diagnosis, and age at diagnosis, patients who experienced a neurotoxic event received an average of 2.25...fewer doses of intrathecal methotrexate," Taylor and colleagues report.

Table. Dose and Treatment Comparison by Neurotoxicity Status

  Neurotoxicity No Neurotoxicity P Value
IV MTX dose, g/m2 10.23 12.04 0.084
Number of IT MTX doses 8.84 11.09 <0.01
Time to maintenance 296.9 days 290.0 days 0.408
IT MTX, intrathecal methotrexate


When doses were modified, the most common form of dose modification was to hold lumbar punctures and replace intrathecal methotrexate with intrathecal cytarabine/hydrocortisone for at least one subsequent lumbar puncture after the patient experienced the event.

This was followed by holding at least the next scheduled lumbar puncture and resuming intrathecal methotrexate given together with leucovorin rescue, the investigators explain.

The investigators note that lumbar punctures were generally held for 4 to 6 weeks in order for symptoms to resolve or at least for the abnormality to improve on MRI.

The majority of patients who experienced methotrexate neurotoxicity (61.5%) were retreated with intrathecal methotrexate and leucovorin rescue, but 17.9% of affected patients were never rechallenged, the researchers note.

Thirteen percent of affected patients continued to receive intrathecal methotrexate with leucovorin without interruption of previously scheduled therapy.

As for relapse, 15.4% of those who developed neurotoxicity experienced relapse during the study interval, compared with only 2.1% of patients who did not.

"Similarly, CNS [central nervous system] relapse was significantly more frequent among patients with neurotoxicity (10.3%) than patients without neurotoxicity (2.1%)," the authors note.

Poorer Outcomes

Senior author Michael Scheurer, PhD, MPH, Baylor College of Medicine, Houston, Texas, noted that a number of factors could contribute to an increased risk for poorer outcomes among minority children, including lack of access to care, delayed diagnosis, lack of compliance with therapy, as well as toxicities leading to delays in therapy.

There may even be biological differences in the disease in minority children, he added.

"For example, we now understand that some Hispanic children have different genetic mutations in their leukemia cells that place them at a higher risk for relapse," Scheurer said in an email to Medscape Medical News.

"Therefore, their treatment regimen may be a little more aggressive, which could contribute to more toxicities," he elaborated.

Until oncologists better understand what predisposes patients to develop neurotoxicity, "I think one way that we could address this issue is to educate parents on the early signs of toxicity so that they can alert their oncologist as soon as these signs begin," Scheurer suggested.

For example, the child could be having difficulty with memory — eg, with remembering certain words — or changes might occur in the child's handwriting.

"Episodes of neurotoxicity can be mitigated by giving other rescue drugs, such as leucovorin, or by delaying the next dose of methotrexate temporarily," Scheurer added.

"And as our knowledge continues to grow on the risk factors [that predispose children] to adverse effects from methotrexate, we can begin to develop more personalized treatment programs to overcome them or screen for these effects earlier in those patients we know are more likely to experience them," he observed.

The study was supported by the National Institutes of Health and the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, St. Baldrick's Foundation Consortium Research Grant. The authors have disclosed no relevant financial relationships.

Clin Cancer Res. Published online September 11, 2018. Abstract

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