Methotrexate-Induced Neurotoxicity in Hispanic Adolescents with High-Risk Acute Leukemia—A Case Series

Giordano, Lisa; Akinyede, Oyinade; Bhatt, Nidhi; Dighe, Dipti; Iqbal, Asneha

doi:10.1089/jayao.2016.0094

Cited by 8 publications

(10 citation statements)

References 22 publications

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“…Of the patients who experienced a neurotoxic event in our cohort, 74.4% were Hispanic, and, of the patients who experienced a second neurotoxic event, all were Hispanic. Our suggestion that Hispanics are at an increased risk of developing MTX neurotoxicity is supported by two recent case series which also reported high proportion of Hispanic patients with subacute neurotoxicity (11,12). Specifically, Afshar et al, reported on 18 cases of neurotoxicity, of which 66.7% (n=12) were Hispanic (11).…”

Section: Discussionsupporting

confidence: 69%

“…Specifically, Afshar et al, reported on 18 cases of neurotoxicity, of which 66.7% (n=12) were Hispanic (11). Similarly, Giordano et al, described a series of five Hispanic patients who developed MTX neurotoxicity (12).…”

Section: Discussionmentioning

confidence: 97%

“…Several recent case series have reported a high prevalence of MTX subacute neurotoxicity among Hispanic patients with ALL suggesting sensitivity to MTX therapy may differ by race and ethnicity (11,12). Disparities and mortality in pediatric ALL have been narrowing over time (13–15).…”

Section: Introductionmentioning

confidence: 99%

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Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients

Taylor

Brown

Brackett

et al. 2018

Clinical Cancer Research

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Methotrexate chemotherapy can be associated with neurologic complications during therapy and long-term neurologic deficits. This study evaluated demographic and clinical factors associated with incidence of methotrexate neurotoxicity and described the impact of neurotoxicity on acute lymphoblastic leukemia (ALL) therapy in pediatric patients. Patients were enrolled between 2012 and 2017 from three pediatric cancer treatment centers in the United States. Medical records for suspected cases of methotrexate neurotoxicity, defined as an acute neurologic event following methotrexate therapy, were reviewed. Cox proportional hazards models were used to estimate the association between race/ethnicity and methotrexate neurotoxicity. Multivariable linear regression models compared treatment outcomes between patients with and without methotrexate neurotoxicity. Of the 280 newly diagnosed patients enrolled, 39 patients (13.9%) experienced methotrexate neurotoxicity. Compared with non-Hispanic whites, Hispanic patients experienced the greatest risk of methotrexate neurotoxicity (adjusted HR, 2.43; 95% CI, 1.06-5.58) after accounting for sex, age at diagnosis, BMI -score at diagnosis, and ALL risk stratification. Patients who experienced a neurotoxic event received an average of 2.25 fewer doses of intrathecal methotrexate. Six of the 39 cases of neurotoxicity (15.4%) experienced relapse during the study period, compared with 13 of the 241 (2.1%) patients without neurotoxicity ( = 0.0038). Hispanic ethnicity was associated with increased risk of methotrexate neurotoxicity, which was associated with treatment modifications and relapse. Understanding the mechanism and predictors of methotrexate neurotoxicity is important to improving treatment outcomes in pediatric ALL. .

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 97%

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Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients

Taylor

Brown

Brackett

et al. 2018

Clinical Cancer Research

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“…MTX is the most commonly used disease-modifying anti-rheumatic agent and is also effective at treating patients with breast cancer ( 28 , 29 ). Previous studies have demonstrated that MTX induces greater cytotoxicity and growth inhibition in leukemia and other malignant cell types compared with other treatments ( 30 , 31 ). It has been demonstrated that sustained ERS is a major contributor to MTX-induced cell death, as indicated by the induction of several unfolded protein response markers, which ultimately induce apoptosis ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Methotrexate remediates spinal cord injury inï¿½vivo and inï¿½vitro via suppression of endoplasmic reticulum stress-induced apoptosis

et al. 2018

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It has been suggested that endoplasmic reticulum stress (ERS) may induce apoptosis following spinal cord injury (SCI). Methotrexate (MTX) has been used as a long-term therapy regimen for rheumatoid arthritis. However, it is not clear whether MTX remediates SCI by inhibiting ERS. In the present study, to establish an in vitro ERS cell model, PC12 cells were pre-incubated with triglycerides (TG). MTT assays revealed that treatment with 1, 2.5, 5 and 10 µM TG decreased PC12 cell viability in a dose-dependent manner. Additionally, MTX treatment significantly reversed the TG-induced decrease in cell viability and increased apoptosis according to the flow cytometry assay (P<0.05). Notably, western blotting indicated that MTX significantly decreased levels of glucose-regulated protein (GRP)78, CCAAT-enhancer-binding protein homologous protein (CHOP) and caspase-12 expression (P<0.05), which were increased following treatment with TG. Furthermore, the in vivo role of MTX in a rat model of SCI was evaluated. The motor behavioral function of rats was improved following treatment with MTX according to Basso, Beattie and Bresnahan scoring (P<0.05). Terminal deoxynucleotidyl-transferase-mediated dUTP nick end staining indicated that there were no apoptotic cells present in sham rats. In the SCI model group, apoptotic cells were observed at day 7; however, the number of apoptotic cells was reduced following an additional 7 days of MTX administration. Furthermore, levels of ERS-associated proteins, including caspase-3, activating transcription factor 6, serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α, eukaryotic initiation factor 2 α and GRP78, were significantly increased following SCI; however, administration of MTX for 7 days significantly reversed this effect (P<0.05, P<0.01 and P<0.001). Therefore, MTX may improve SCI by suppressing ERS-induced apoptosis in vitro and in vivo.

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“…It is administered intravenously, orally and intrathecally, the latter largely replacing cranial and spinal radiotherapy in the 1990's as a method to eradicate leukaemic cells from the CNS, reducing the risk of relapse. However, both acute and chronic neurological side effects are reported following methotrexate use, including seizures, leukoencephalopathy and strokelike syndrome 5,[30][31][32] . Additionally, long-term neurotoxicity manifesting as neurocognitive impairment is an emerging concern affecting a substantial number of childhood leukaemia survivors [33][34][35] .…”

Section: Methotrexate Use In Leukaemiamentioning

confidence: 99%

Should nitrous oxide ever be used in oncology patients receiving methotrexate therapy?

Forster

Bell

Halsey

2019

Pediatric Anesthesia

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Nitrous oxide (N2O) is frequently used for short anaesthesia/analgesia in children undergoing painful or repetitive procedures 1. Children with acute lymphoblastic leukaemia (ALL) require repeated lumbar punctures with direct instillation of intrathecal chemotherapy, usually the anti-folate agent Methotrexate, during their treatment. These procedures are frequently performed under anaesthesia. Concerns have been intermittently raised about a drug-interaction between methotrexate and N2O that may potentiate the undesirable side effects of methotrexate, including neurotoxicity. However, the clinical evidence consists mainly of isolated case reports leading to a lack of consensus amongst paediatric anaesthetists about the relative risk-benefits of using N2O in children with ALL. In this article, we review the biochemical basis and scientific observations that suggest a significant interaction between N2O and methotrexate due to their dual inhibition of the key enzyme methionine 2 synthase. The possible role of this interaction in potentiating neurotoxicity in children with cancer is discussed, and arguments and counter-arguments about the clinical significance of this largely theoretical relationship are explored. Following comprehensive review of all the available data we make the case for the circumstantial evidence being sufficiently compelling to prompt a review of practice by paediatric anaesthetists and call for a precautionary approach by avoiding the use of N2O in children receiving concurrent methotrexate.

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Methotrexate-Induced Neurotoxicity in Hispanic Adolescents with High-Risk Acute Leukemia—A Case Series

Cited by 8 publications

References 22 publications

Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients

Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients

Methotrexate remediates spinal cord injury inï¿½vivo and inï¿½vitro via suppression of endoplasmic reticulum stress-induced apoptosis

Should nitrous oxide ever be used in oncology patients receiving methotrexate therapy?

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