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Biomarkers may predict poor neurologic outcomes among pediatric leukemia survivors
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The increased risk for long-term complications with attention, organization and other neurocognitive skills among survivors of pediatric acute lymphoblastic leukemia may be caused by the malignancy itself, according to researchers at St. Jude Children’s Research Hospital.
“Until now, we had not suspected that leukemia by itself, or the inflammatory response to the disease, may lead to changes that leave ALL survivors at risk for problems with executive functioning and processing speed later,” Kevin R. Krull, PhD, member of the faculty in the department of epidemiology and cancer control at St. Jude, said in a press release.
Krull and colleagues examined the cerebrospinal fluid of 138 long-term survivors of pediatric ALL treated with chemotherapy alone between 2000 and 2010. Investigators looked for proteins and biomarkers of brain cell damage associated with either high-dose IV methotrexate or methotrexate delivered into the spinal fluid.
Methotrexate treatment appeared associated with biomarkers that signaled as much as a 70% increased risk for reduced neurocognitive functioning among long-term survivors.
HemOnc Today spoke with Krull about the study results and their potential implications, the steps that can be taken to identify survivors at risk for neurocognitive problems and allow for early intervention, and what still must be confirmed in future research.
Question: Can you provide an overview of how you made this discovery?
Answer: As part of a grant funded by NCI, we identified eligible survivors of childhood ALL who were treated on the Total 15 study protocol at St. Jude Children’s Research Hospital, and who agreed to cerebrospinal fluid collection as part of the protocol. Cerebrospinal fluid is readily accessible during diagnostic and therapeutic lumbar punctures, so no additional lumbar punctures for research-only purposes were required. We assayed cerebrospinal fluid collected prior to any treatment, such as diagnostic lumbar puncture, and after major treatment phases for proteins that are known biomarkers of brain glial cell and neuronal cell integrity. We compared changes in these biomarkers over the course of therapy and linked the biomarker patterns to neurocognitive testing and brain imaging studies collected when the survivors were aged at least 8 years old and 2 years after therapy completion.
Q: What are the implications of this discovery?
A: The study has implications for both understanding the mechanisms of brain injury in survivors of ALL, which can help guide future intervention trials as well as the prediction of which children may be at greatest risk for long-term problems. The study reveals that brain glial cell injury begins prior to any cancer therapy, possibly due to neuroinflammation, and increases following intrathecal and high-dose systemic methotrexate therapy. Neuronal cell injury begins approximately 2 months after the start of therapy and is associated with dose of intrathecal methotrexate. One of the biomarkers of neuronal cell injury, tau protein, is predictive of long-term brain injury more than 5 years after the protein was detected.
Q: Did the findings surprise you?
A: We were surprised by the findings of brain glial cell injury prior to the start of any chemotherapy treatment. This is likely the result of disease-based inflammatory cytokines, which may cross the blood-brain-barrier and initiate a neuroinflammatory process, including microglial activation. Prior to our study, chemotherapy exposure was identified as the main cause of brain injury.
Q: What steps can be taken to identify survivors at risk for neurocognitive problems and allow for early intervention?
A: Monitoring tau protein in routine lumbar punctures prior to administration of intrathecal chemotherapy may help to identify those patients at greatest risk for future brain injury. The only step that need be added to routine care would be to sample the cerebrospinal prior to injecting the chemotherapy agents and then assay the sample for tau protein. In our study, tau protein peaked approximately 2 months following the start of chemotherapy, and those patients with the highest elevation in tau had the greatest risk for future brain dysfunction. Those patients with elevated tau protein could be enrolled in preventive interventions to support neural development prior to manifestation of long-term impairment.
Q: What still must be confirmed in future research?
A: Ideally, our results would be cross-validated with an independent sample of survivors. We are in the process of extending this work with children treated on a more recent protocol.
Q: Is there anything else that you would like to mention?
A: Our data suggests brain injury begins very early during the course of chemotherapy. Although many children do not demonstrate functional limitations until between 1 and 2 years following the completion of therapy, interventions for those who are at greatest risk do not need to wait until the functional impairment is displayed. Stimulation of brain networks, particularly those involved in processing speed and executive function, can begin prior to therapy completion. Hopefully such stimulation will prevent or limit the functional limitations from being manifested later. – by Jennifer R. Southall
Reference:
Cheung YT, et al. JAMA Oncol. 2018;doi:10.1001/jamaoncol.2018.0089.
For more information:
Kevin R. Krull, PhD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.
Disclosure: Krull reports no relevant financial disclosures.