Association of Cerebrospinal Fluid Biomarkers of Central Nervous System Injury With Neurocognitive and Brain Imaging Outcomes in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia

Cheung, Yin Ting; Khan, Raja B.; Liu, Wei; Brinkman, Tara M.; Edelmann, Michelle N.; Reddick, Wilburn E.; Pei, Deqing; Panoskaltsis‐Mortari, Angela; Srivastava, Deokumar; Cheng, Cheng; Robison, Leslie L.; Hudson, Melissa M.; Pui, Ching Hon; Krull, Kevin R.

doi:10.1001/jamaoncol.2018.0089

Cited by 47 publications

(50 citation statements)

References 27 publications

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“…Early autopsy studies suggest that the majority of leukemia patients would develop CNS disease during the course of the disease [8]. Hence, irrespective of the initial CNS status, all patients are treated with potent intrathecal prophylactic chemotherapy (methotrexate in most protocols), for which an association with neuronal injury and leukoencephalopathy has been shown [9]. Currently known risk factors for CNS involvement in ALL include peripheral hyperleukocytosis upon diagnosis and a T cell immunophenotype [3].…”

Section: Cns Involvement In All: a Clinical Challengementioning

confidence: 99%

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Lenk

Alsadeq

Schewe

2020

Cancer Metastasis Rev

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Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. One of the major clinical challenges is adequate diagnosis and treatment of central nervous system (CNS) involvement in this disease. Intriguingly, there is little solid evidence on the mechanisms sustaining CNS disease in ALL. Here, we present and discuss recent data on this topic, which are mainly derived from preclinical model systems. We thereby highlight sites and routes of leukemic CNS infiltration, cellular features promoting infiltration and survival of leukemic cells in a presumably hostile niche, and dormancy as a potential mechanism of survival and relapse in CNS leukemia. We also focus on the impact of ALL cytogenetic subtypes on features associated with a particular CNS tropism. Finally, we speculate on new perspectives in the treatment of ALL in the CNS, including ideas on the impact of novel immunotherapies.

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Section: Cns Involvement In All: a Clinical Challengementioning

confidence: 99%

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Lenk

Alsadeq

Schewe

2020

Cancer Metastasis Rev

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“…With regard to underlying pathology, Cheung et al recently associated elevated cerebrospinal values of total tau and myelin basic protein with development of leukoencephalopathy . This suggests underlying neural damage, which could be axonal injury (e.g., demyelination).…”

Section: Discussionmentioning

confidence: 99%

Long‐term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high‐dose intravenous chemotherapy

Sleurs

Lemiere

Radwan

et al. 2019

Pediatric Blood & Cancer

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Purpose: Knowledge is limited regarding the prevalence and persistence of chemotherapyinduced leukoencephalopathy in childhood sarcoma patients. This study explored the presence, clinical relevance, and potential risk factors of leukoencephalopathy in childhood bone and soft tissue sarcoma survivors, treated with intravenous chemotherapy. Methods:We acquired cross-sectional neurocognitive data in adult survivors (n = 34) (median age at diagnosis [AaD] = 13.32 years, age range = 16-35 years) and healthy age-matched controls (n = 34). Additionally, magnetic resonance imaging included T2-weighted FLAIR (leukoencephalopathy Fazekas rating), multiexponential T2 relaxation (MET2), and multishell diffusion MRI to estimate myelin integrity-related metrics and fluid movement restrictions. Finally, chemotherapy subgroups (methotrexate, alkylating agents, or combination), AaD, and Apo and MTHFRC677T polymorphisms were explored as potential risk factors for leukoencephalopathy. Results:At the group level, quality of life, working memory, processing speed, and visual memory were significantly lower in patients compared to controls. Furthermore, long-term leukoencephalopathy was observed in 27.2% of the childhood sarcoma survivors, which was related to attentional processing speed. Lesions were related to diffusion-derived, but not to myelinsensitive metrics. A significant interaction effect between AaD and chemotherapy group demonstrated more lesions in case of high-dose methotrexate (HD-MTX) (F = 3.434, P = .047). However, patients treated with alkylating agents (without HD-MTX) also showed lesions in younger patients. Genetic predictors were nonsignificant. Conclusion and implication:This study suggests long-term leukoencephalopathy with possibly underlying changes in vasculature, inflammation, or axonal injury, but not necessarily long-term demyelination. Such lesions could affect processing speed, and as such long-term daily life functioning of these patients.

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“…-Damage of the hippocampus and other areas involved in memory emotion circuits (amygdala, thalamus, striatum, substantia nigra/ventral tegmental area) [10,[29][30][31][32] -Dendrite and axonal growth damage [10] • damage of prefrontal functions [29,31,32,35,36] • brain connectivity disruption [34] • leukoencephalopathy [13,36] -Increase in tau protein (axonal damage and neurodegeneration), increase in GFAP (associated with attention deficit) [36] • neuroinflammation (increase in C-reactive protein, IL, and tumor necrosis factorα) [9,26,31,32] • hypothalamic-pituitary-adrenal axis alteration [37] The relationship and interactions between pediatric cancer, chemotherapy, sleep and CNS development/damage and cognitive function are complex and schematically represented in Figure 1. The above results highlight the need for interventions that prevent or manage cognitive impairment in pediatric ALL; in recent years, the results of cognitive behavioral therapy (CBT) and physical activity in pediatric patients with ALL or solid CNS tumors have been examined, with improvement of brain function and an increase in white matter and hippocampal volume [38][39][40].…”

Section: Pediatric Cancer As a Cause Of Neurodevelopmental Disordersmentioning

confidence: 99%

Neurodevelopmental Consequences of Pediatric Cancer and Its Treatment: The Role of Sleep

et al. 2020

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Cognitive impairment is frequent in pediatric cancer, and behavioral and psychological disturbances often also affect children who have survived cancer problems. Furthermore, pediatric tumors are also often associated with sleep disorders. The interrelationship between sleep disorders, neurodevelopmental disorders and pediatric cancer, however, is still largely unexplored. In this narrative review we approach this important aspect by first considering studies on pediatric cancer as a possible cause of neurodevelopmental disorders and then describing pediatric cancer occurring as a comorbid condition in children with neurodevelopmental disorders. Finally, we discuss the role of sleep disorders in children with cancer and neurodevelopmental disorders. Even if the specific literature approaching directly the topic of the role of sleep in the complex relationship between pediatric cancer and neurodevelopmental disorders was found to be scarce, the available evidence supports the idea that in-depth knowledge and correct management of sleep disorders can definitely improve the health and quality of life of children with cancer and of their families.

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Association of Cerebrospinal Fluid Biomarkers of Central Nervous System Injury With Neurocognitive and Brain Imaging Outcomes in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia

Abstract: Glial injury may be present at diagnosis of ALL. Neuronal injury was associated with intrathecal chemotherapy. The CSF biomarkers may be useful in identifying individuals at risk for worse neurologic outcomes, particularly those with genetic susceptibility to poor brain function.

Cited by 47 publications

References 27 publications

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

Long‐term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high‐dose intravenous chemotherapy

Neurodevelopmental Consequences of Pediatric Cancer and Its Treatment: The Role of Sleep

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