Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

Bhojwani, Deepa; Sabin, Noah D.; Pei, Deqing; Yang, Jun J.; Khan, Raja B.; Panetta, John C.; Krull, Kevin R.; Inaba, Hiroto; Rubnitz, Jeffrey E.; Metzger, Monika L.; Howard, Scott C.; Ribeiro, Raul C.; Cheng, Cheng; Reddick, Wilburn E.; Jeha, Sima; Sandlund, John T.; Evans, William E.; Pui, Ching‐Hon; Relling, Mary V.

doi:10.1200/jco.2013.53.0808

Cited by 303 publications

(329 citation statements)

References 43 publications

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“…In the current cohort, incidence of methotrexate related encephalopathy was 4.8%, and all cases developed neurotoxicity in relation to IT MTX. Comparable incidence was reported by Bhojwani et al [8], who reported 3.8% clinical neurotoxicity, but mostly related to high dose IV MTX [8].…”

Section: Discussionsupporting

confidence: 47%

Methotrexate Induced Encephalopathy in Acute Lymphoblastic Leukemia in Omani Children

Nazir¹

2017

HTIJ

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Objectives: To investigate the incidence and clinical profile of methotrexate related encephalopathy in Omani children with pre-B Acute Lymphoblastic Leukemia (ALL). Methods:A retrospective cohort study of 8 children with Pre B Acute Lymphoblastic Leukemia who developed encephalopathy while being treated according to United Kingdome Research Council (UK MRC) ALL protocol during the period between [2005][2006][2007][2008][2009][2010][2011][2012][2013][2014][2015][2016]. Demographic data, clinical presentation, diagnosis and treatment are discussed.Results: Eight children (4 males,4 females), 7 of them were above 10 years of age, with ALL treated according to intermediate risk UK MRC ALL protocol developed transient encephalopathy during treatment. Six children had one episode, one had two episodes, and last one had 3 episodes. All except one recovered completely within 24-96 hours after symptomatic treatment. This one had extensive neurological involvement and took seven days to recover. All children had normal coagulation and thrombophilia studies. Four out of the 8 patients subsequently received intrathecal (IT) cytarabine instead of methotrexate without any neurotoxicity. The other 4 patients received further IT methotrexate. Three of these four had recurrence on re-challenge, while the fourth remained asymptomatic. Seven children with neurotoxicity had MRI findings of white matter changes. Six out of eight children are in complete remission while two died later following relapse. Conclusion:Methotrexate induced encephalopathy can occur after intrathecal methotrexate treatment especially in children older than 10 years of age. Diffusion weighted MRI is the currently available best diagnostic tool. Treatment of methotrexate neurotoxicity is mainly supportive and recovery is usually complete. Further studies are needed to understand the mechanism of neurotoxicity, risk factors, and to define the safe dose to prevent such neurotoxicity.

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Section: Discussionsupporting

confidence: 47%

Methotrexate Induced Encephalopathy in Acute Lymphoblastic Leukemia in Omani Children

Nazir¹

2017

HTIJ

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“…Leukoencephalopathies immediately following intrathecal methotrexate treatments are a well-known risk (Reddick et al, 2005). There is some indication that susceptibility may relate to particular gene variants, many of which are involved in neurogenesis (Bhojwani et al, 2014). Methotrexate has been shown to disrupt oligodendroglial progenitor cells and phospholipids important for myelination and white matter development (Krull et al, 2013b;Monje and Dietrich, 2012).…”

Section: Figmentioning

confidence: 99%

“…Neuroimaging studies indicate that alterations of brain structure and function represent the final common biological pathway resulting in cognitive deficit. Few neuroimaging studies have been conducted to date, but white matter pathology is the most consistent finding (Bhojwani et al, 2014;Edelmann et al, 2014;ElAlfy et al, 2014;Kesler et al, 2010;Morioka et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

et al. 2016

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Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk for cognitive impairments that disrupt everyday functioning and decrease quality of life. The specific biological mechanisms underlying cognitive impairment following ALL remain largely unclear, but previous studies consistently demonstrate significant white matter pathology. We aimed to extend this literature by examining the organization of the white matter connectome in young patients with a history of ALL treated with chemotherapy only. We applied graph theoretical analysis to diffusion tensor imaging obtained from 31 survivors of ALL age 5-19 years and 39 matched healthy controls. Results indicated significantly lower small-worldness ( p = 0.007) and network clustering coefficient ( p = 0.019), as well as greater cognitive impairment ( p = 0.027) in the ALL group. Regional analysis indicated that clustered connectivity in parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions was altered in the ALL group. Random forest analysis revealed a model of connectome and demographic variables that could automatically classify survivors of ALL as having cognitive impairment or not (accuracy = 0.89, p < 0.0001). These findings provide further evidence of brain injury in young survivors of ALL, even those without a history of central nervous system (CNS) disease or cranial radiation. Efficiency of local information processing, reorganization of hub connectivity, and cognitive reserve may contribute to cognitive outcome in these children. Certain connectome properties showed U-shaped relationships with cognitive impairment suggesting an optimal range of regional connectivity.

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“…50,99 Despite multiple candidate-gene studies for toxicity, results have been conflicting (or based on single, nonreplicated small studies), and thus it is currently not possible to recommend changes to methotrexate dosing based on inherited variants in these candidate genes. 97,98 Genome-wide studies identified variants associated with leukoencephalopathy, 100 but these findings have not yet been replicated. Methotrexate effects are influenced by interindividual variation in its plasma clearance, leading some to implement an approach that targets systemic exposure based on clearance.…”

Section: Vincristinementioning

confidence: 99%

Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama

Relling

Yang

2015

Blood

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127

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Although somatically acquired genomic alterations have long been recognized as the hallmarks of acute lymphoblastic leukemia (ALL), the last decade has shown that inherited genetic variations (germline) are important determinants of interpatient variability in ALL susceptibility, drug response, and toxicities of ALL therapy. In particular, unbiased genome-wide association studies have identified germline variants strongly associated with the predisposition to ALL in children, providing novel insight into the mechanisms of leukemogenesis and evidence for complex interactions between inherited and acquired genetic variations in ALL. Similar genome-wide approaches have also discovered novel germline genetic risk factors that independently influence ALL prognosis and those that strongly modify host susceptibility to adverse effects of antileukemic agents (eg, vincristine, asparaginase, glucocorticoids). There are examples of germline genomic associations that warrant routine clinical use in the treatment of childhood ALL (eg, TPMT and mercaptopurine dosing), but most have not reached this level of actionability. Future studies are needed to integrate both somatic and germline variants to predict risk of relapse and host toxicities, with the eventual goal of implementing genetics-driven precision-medicine approaches in ALL treatment.

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Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

Cited by 303 publications

References 43 publications

Methotrexate Induced Encephalopathy in Acute Lymphoblastic Leukemia in Omani Children

Methotrexate Induced Encephalopathy in Acute Lymphoblastic Leukemia in Omani Children

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

Inherited genetic variation in childhood acute lymphoblastic leukemia

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