Feature

Hispanic children with acute lymphoblastic leukemia at higher risk for neurotoxicity

Michael E. Scheurer

Hispanic children with acute lymphoblastic leukemia appeared more likely than non-Hispanic patients to develop neurotoxicity during methotrexate chemotherapy, according to study results.

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, and colleagues analyzed medical records of 280 pediatric patients with newly diagnosed ALL.

All patients received methotrexate, a standard component of ALL treatment.

Thirty-nine patients (13.9%) developed neurotoxicity, defined as altered mental status, stroke or seizure due to treatment. When researchers controlled for age at diagnosis, sex, BMI and disease risk, they determined Hispanic patients were twice as likely as non-Hispanics to develop neurotoxicity.

Nine of the 39 patients experienced a second event, all of whom were Hispanic.

Patients who developed neurotoxicity received on average 2.25 fewer doses of intrathecal methotrexate. Although not completely understood, this treatment modification could lead to reduced treatment effectiveness.

Six (15.4%) of the 39 patients who developed neurotoxicity experienced disease relapse, compared with 13 (2.1%) of the 241 patients who did not develop neurotoxicity.

The study included minority patients from other racial or ethnic groups; however, those populations were too small to draw definitive conclusions about neurotoxicity frequency, according to researchers.

HemOnc Today spoke with Scheurer about the study, the potential implications of the results, and the questions that must be addressed in future research.

 

Question: What prompted you to conduct this study?

Answer: We had an ongoing study in which we were looking at symptom burdens among our pediatric patients with ALL. Neurotoxicity is not new in this population, but our clinical research manager noticed it seemed to be happening more among our Hispanic patients than others.

 

Q: How did you conduct the study?

A: We enrolled patients newly diagnosed with ALL, and we collected biospecimens and symptom data at several key time points during their therapy. When we decided to look at the neurotoxicity outcome, we went back to the medical records to identify those who had events. We categorized them based on the types of symptoms they presented with in terms of neurotoxic events. We also assessed whether patients developed second events.

 

Q: What did you find?

A: Overall, the incidence of neurotoxic events was a bit higher than what other studies had reported. Our patient population included a higher proportion of Hispanic patients than most other studies. An overwhelming majority of patients who had a neurotoxic event were Hispanic, and all patients who developed a second neurotoxic event were Hispanic.

 

Q: Did the results surprise you?

A: We were not surprised in the sense that it confirmed the trend we noticed just by reviewing some of the data, but we were a little surprised to see the overall size of the effect was so large, with a twofold risk among Hispanic patients compared with non-Hispanics.

 

Q: What are the potential explanations for higher neurotoxicity rates among Hispanic children?

A: We are very interested in trying to better understand that. In general, leukemia looks a bit different among Hispanic patients. They have different types of mutations in the DNA of their leukemia cells than other patients. The disease biology is a bit different, and that could contribute to a higher rate of neurotoxicity. There are genetic variants related to the way individuals metabolize certain drugs, so perhaps the way Hispanics metabolize methotrexate could explain the neurotoxicity. If so, can we identify patients upfront who might be more sensitive to methotrexate and maybe modify their dose without risking the good survival rate we have for leukemia? Or, could we monitor them more closely in hopes of identifying neurotoxicity sooner?

A majority of ALL therapy is administered in the outpatient setting, so we can educate parents about neurotoxicity signs and symptoms. They could include slight changes in speech, handwriting or gait, or they could be something more serious like a seizure.

Q: Should standard treatment for Hispanic children with ALL be modified upfront due to the elevated risk for neurotoxicity?

A: I think the risk-adapted chemotherapy approach we use works very well. Overall, cure rates are 85% to 90%, and we don’t want to jeopardize that. If we start modifying doses early, does that impact the chance for cure? We definitely don’t want to do that. If we do a better job predicting which patients are at highest risk, there are ways we can monitor for these toxicities.

One thing physicians can do when they identify neurotoxicity is provide leucovorin, which counteracts the effects of the methotrexate. Once that is administered, the neurotoxicity usually resolves. However, once a person has had one event, it is likely they will have a second event once high levels of methotrexate are re-initiated.

 

Q: Is more research warranted to determine whether the elevated risk for neurotoxicity extends beyond Hispanic children to those from other minority populations?

A: Absolutely. Non-Hispanic whites and Hispanic children have the highest rates of leukemia. Non-Hispanic black and Asian children typically have low rates of ALL. To study these effects in non-Hispanic black or Asian children, we will have to do much larger studies that include more sites than we included in our study.

 

Q: Your research team is examining whether biomarkers can predict neurotoxicity. How are you conducting this investigation and what do you hope to find?

A: We are looking for variability in genes related to the metabolism of methotrexate, as well as variability in genes that may be related to normal brain functioning that might also be affected or triggered by the methotrexate. Our ultimate goals are to predict patients who are most likely to develop neurotoxic events and to identify any biomarkers we can monitor over the course of therapy to make that prediction before the physical signs or symptoms occur.

 

Q: Is there anything else you would like to mention?

A: There is still a lot to learn about how some of the therapies impact certain patients and families. It is important we educate our patients about the signs and symptoms of side effects, especially neurotoxic events, and make sure they are reporting them to their oncologists as soon as possible. – by Scott Buzby

 

Reference:

Taylor OA, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-18-0939.

 

For more information:

Michael E. Scheurer , PhD, MPH, can be reached at scheurer@bcm.edu.

 

Disclosures: The study was supported by NIH and the Reducing Ethnic Disparities in Acute Leukemia Consortium, as well as a grant from St. Baldrick’s Foundation. Scheurer reports no relevant financial disclosures.

Michael E. Scheurer

Hispanic children with acute lymphoblastic leukemia appeared more likely than non-Hispanic patients to develop neurotoxicity during methotrexate chemotherapy, according to study results.

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, and colleagues analyzed medical records of 280 pediatric patients with newly diagnosed ALL.

All patients received methotrexate, a standard component of ALL treatment.

Thirty-nine patients (13.9%) developed neurotoxicity, defined as altered mental status, stroke or seizure due to treatment. When researchers controlled for age at diagnosis, sex, BMI and disease risk, they determined Hispanic patients were twice as likely as non-Hispanics to develop neurotoxicity.

Nine of the 39 patients experienced a second event, all of whom were Hispanic.

Patients who developed neurotoxicity received on average 2.25 fewer doses of intrathecal methotrexate. Although not completely understood, this treatment modification could lead to reduced treatment effectiveness.

Six (15.4%) of the 39 patients who developed neurotoxicity experienced disease relapse, compared with 13 (2.1%) of the 241 patients who did not develop neurotoxicity.

The study included minority patients from other racial or ethnic groups; however, those populations were too small to draw definitive conclusions about neurotoxicity frequency, according to researchers.

HemOnc Today spoke with Scheurer about the study, the potential implications of the results, and the questions that must be addressed in future research.

 

Question: What prompted you to conduct this study?

Answer: We had an ongoing study in which we were looking at symptom burdens among our pediatric patients with ALL. Neurotoxicity is not new in this population, but our clinical research manager noticed it seemed to be happening more among our Hispanic patients than others.

 

Q: How did you conduct the study?

A: We enrolled patients newly diagnosed with ALL, and we collected biospecimens and symptom data at several key time points during their therapy. When we decided to look at the neurotoxicity outcome, we went back to the medical records to identify those who had events. We categorized them based on the types of symptoms they presented with in terms of neurotoxic events. We also assessed whether patients developed second events.

 

Q: What did you find?

A: Overall, the incidence of neurotoxic events was a bit higher than what other studies had reported. Our patient population included a higher proportion of Hispanic patients than most other studies. An overwhelming majority of patients who had a neurotoxic event were Hispanic, and all patients who developed a second neurotoxic event were Hispanic.

 

Q: Did the results surprise you?

A: We were not surprised in the sense that it confirmed the trend we noticed just by reviewing some of the data, but we were a little surprised to see the overall size of the effect was so large, with a twofold risk among Hispanic patients compared with non-Hispanics.

 

Q: What are the potential explanations for higher neurotoxicity rates among Hispanic children?

A: We are very interested in trying to better understand that. In general, leukemia looks a bit different among Hispanic patients. They have different types of mutations in the DNA of their leukemia cells than other patients. The disease biology is a bit different, and that could contribute to a higher rate of neurotoxicity. There are genetic variants related to the way individuals metabolize certain drugs, so perhaps the way Hispanics metabolize methotrexate could explain the neurotoxicity. If so, can we identify patients upfront who might be more sensitive to methotrexate and maybe modify their dose without risking the good survival rate we have for leukemia? Or, could we monitor them more closely in hopes of identifying neurotoxicity sooner?

A majority of ALL therapy is administered in the outpatient setting, so we can educate parents about neurotoxicity signs and symptoms. They could include slight changes in speech, handwriting or gait, or they could be something more serious like a seizure.

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Q: Should standard treatment for Hispanic children with ALL be modified upfront due to the elevated risk for neurotoxicity?

A: I think the risk-adapted chemotherapy approach we use works very well. Overall, cure rates are 85% to 90%, and we don’t want to jeopardize that. If we start modifying doses early, does that impact the chance for cure? We definitely don’t want to do that. If we do a better job predicting which patients are at highest risk, there are ways we can monitor for these toxicities.

One thing physicians can do when they identify neurotoxicity is provide leucovorin, which counteracts the effects of the methotrexate. Once that is administered, the neurotoxicity usually resolves. However, once a person has had one event, it is likely they will have a second event once high levels of methotrexate are re-initiated.

 

Q: Is more research warranted to determine whether the elevated risk for neurotoxicity extends beyond Hispanic children to those from other minority populations?

A: Absolutely. Non-Hispanic whites and Hispanic children have the highest rates of leukemia. Non-Hispanic black and Asian children typically have low rates of ALL. To study these effects in non-Hispanic black or Asian children, we will have to do much larger studies that include more sites than we included in our study.

 

Q: Your research team is examining whether biomarkers can predict neurotoxicity. How are you conducting this investigation and what do you hope to find?

A: We are looking for variability in genes related to the metabolism of methotrexate, as well as variability in genes that may be related to normal brain functioning that might also be affected or triggered by the methotrexate. Our ultimate goals are to predict patients who are most likely to develop neurotoxic events and to identify any biomarkers we can monitor over the course of therapy to make that prediction before the physical signs or symptoms occur.

 

Q: Is there anything else you would like to mention?

A: There is still a lot to learn about how some of the therapies impact certain patients and families. It is important we educate our patients about the signs and symptoms of side effects, especially neurotoxic events, and make sure they are reporting them to their oncologists as soon as possible. – by Scott Buzby

 

Reference:

Taylor OA, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-18-0939.

 

For more information:

Michael E. Scheurer , PhD, MPH, can be reached at scheurer@bcm.edu.

 

Disclosures: The study was supported by NIH and the Reducing Ethnic Disparities in Acute Leukemia Consortium, as well as a grant from St. Baldrick’s Foundation. Scheurer reports no relevant financial disclosures.

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