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Differential metabolomic pathway analysis in Malaysian childhood acute lymphoblastic leukemia patients treated with high dose methotrexate.
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  • Rizal Husaini Razali,
  • Lay Kek Teh,
  • Mohd Zaki Salleh,
  • Hishamshah Mohd Ibrahim,
Rizal Husaini Razali
Tengku Ampuan Rahimah Hospital
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Lay Kek Teh

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Mohd Zaki Salleh
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Hishamshah Mohd Ibrahim
Ministry of Health Malaysia
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Background: Methotrexate is the mainstay of the consolidation and maintenance phase of chemotherapy protocol for childhood ALL. The objective of this study was to investigate the changes of the metabolism pathways associated with MTX treatment among the patients. Methods: Two serum samples (pre- and post-) were collected from each of the 38 children with ALL: (i) once the diagnosis was confirmed (pre-MTX) and (ii) after the first high dose of MTX (post-MTX). The samples were analysed using HPLC/MS-QTOF. Data acquisition was performed using Agilent MassHunterTMB.05.00 software for metabolomics analysis. Differential expressions of metabolites were analyzed using univariate Welch’s t-test unequal variance. Compounds were identified using METLIN Database. Pathways and networks analyses were performed using Metaboanalyst. The data set was analysed using Receiving Operator Characteristic (ROC) curve. The identities of compounds that were found to be significant in statistical analysis were reconfirmed by HPLC/ MSMS- QTOF. Results: Metabolites with AUC between 0.7 and 0.9 were xanthine (0.889), oxoglutaric acid (0.770) and alpha-linolenic acid (0.741). The lower expression of xanthine was correlated with a good response to MTX in children with ALL; corresponding to a test sensitivity and specificity of 0.77 and 0.87, respectively. Interestingly, this metabolite had the highest AUC value of 0.889 (95% CI; 0.84 – 0.92) and purine metabolism was the most significant pathway altered in the patients treated with xanthine (p-value of 1.26E-35). Conclusion: Xanthine was inversely correlated with the patients’ responses to MTX in childhood ALL. However, the clinical validity of xanthine requires further analysis.