Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia

Yazıcıoğlu, Burc; Kaya, Zühre; S, Güntekin Ergun; Perçin, Ferda Emriye; Koçak, Ülker; Yenicesu, İdil; Gürsel, Türkiz

doi:10.4274/tjh.2016.0007

Cited by 19 publications

(20 citation statements)

References 36 publications

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“…Finally, according to the aforementioned inclusion and exclusion criteria, 34 studies were included in our systematic review. Of the 34 studies (Laverdière et al, 2002;Kishi et al, 2003;Seidemann et al, 2006;Shimasaki et al, 2006;Imanishi et al, 2007;Ruiz-Argüelles et al, 2007;Ashton et al, 2009;Faganel Kotnik et al, 2010;D'Angelo et al, 2011;Faganel Kotnik et al, 2011;Liu et al, 2011;Chiusolo et al, 2012;Erčulj et al, 2012;Haase et al, 2012;Fukushima et al, 2013;Radtke et al, 2013;Yanagimachi et al, 2013;Avivi et al, 2014;Erculj et al, 2014;Suthandiram et al, 2014;den Hoed et al, 2015;Ma et al, 2015;Huang et al, 2016;Tsujimoto et al, 2016;Choi et al, 2017;Giletti et al, 2017;Liu et al, 2017;Yang et al, 2017;Yazıcıoğlu et al, 2017;Oosterom et al, 2018;Chae et al, 2020;Esmaili et al, 2020;Kotur et al, 2020;Chang et al, 2021) included, 31 studies were included in the meta-analysis and three studies were only included for the descriptive analysis since the meta-analysis was infeasible.…”

Section: Electronic Searches and Study Selectionmentioning

confidence: 99%

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

Song

Liu

et al. 2021

Front. Pharmacol.

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Objective: High-dose methotrexate (HDMTX) is a mainstay therapeutic agent for the treatment of diverse hematological malignancies, and it plays a significant role in interindividual variability regarding the pharmacokinetics and toxicity. The genetic association of HDMTX has been widely investigated, but the conflicting results have complicated the clinical utility. Therefore, this systematic review aims to determine the role of gene variants within the HDMTX pathway and to fill the gap between knowledge and clinical practice.Methods: Databases including EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Clinical Trials.gov were searched from inception to November 2020. We included twelve single-nucleotide polymorphisms (SNPs) within the HDMTX pathway, involving RFC1, SLCO1B1, ABCB1, FPGS, GGH, MTHFR, DHFR, TYMS, and ATIC. Meta-analysis was conducted by using Cochrane Collaboration Review Manager software 5.3. The odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were analyzed to evaluate the associations between SNPs and clinical outcomes. This study was performed according to the PRISMA guideline.Results: In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving MTHFR, RFC1, ABCB1, SLCO1B1, TYMS, FPGS, and ATIC genes were investigated, while none of studies reported the polymorphisms of GGH and DHFR yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: MTHFR 677C>T and hepatotoxicity (dominant, OR=1.52, 95% CI=1.03-2.23; recessive, OR=1.68, 95% CI=1.10–2.55; allelic, OR=1.41, 95% CI=1.01–1.97), mucositis (dominant, OR=2.11, 95% CI=1.31–3.41; allelic, OR=1.91, 95% CI=1.28–2.85), and renal toxicity (recessive, OR=3.54, 95% CI=1.81–6.90; allelic, OR=1.89, 95% CI=1.18–3.02); ABCB1 3435C>T and hepatotoxicity (dominant, OR=3.80, 95% CI=1.68-8.61), whereas a tendency toward the decreased risk of HDMTX toxicity was present in three SNPs: TYMS 2R>3R and mucositis (dominant, OR=0.66, 95% CI=0.47–0.94); RFC1 80A>G and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16–0.76); and MTHFR 1298A>C and renal toxicity (allelic, OR=0.41, 95% CI=0.18–0.97). Since the data of prognosis outcomes was substantially lacking, current studies were underpowered to investigate the genetic association.Conclusions: We conclude that genotyping of MTHFR and/or ABCB1 polymorphisms prior to treatment, MTHFR 677C>T particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.

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Section: Electronic Searches and Study Selectionmentioning

confidence: 99%

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

Song

Liu

et al. 2021

Front. Pharmacol.

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“…These studies included a low number of patients (n=21 and n=35, respectively), whereas the studies that did not result in significance were performed in cohorts of 106,32 161,26 and 12727 patients. Since our previous review found no association in 5 of the 6 studies that analyzed anemia and the one that showed association was performed in a population of 37 patients,33 we can conclude that A1298C variant is not a good marker for anemia.…”

Section: A1298c Polymorphism Analysismentioning

confidence: 99%

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

Umerez¹,

Gutiérrez-Camino²,

Muñoz-Maldonado³

et al. 2017

PGPM

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Methotrexate (MTX) is an important component in the therapy used to treat childhood acute lymphoblastic leukemia (ALL). Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for MTX pharmacokinetics. Two single-nucleotide polymorphisms in MTHFR gene, C677T and A1298C, affecting MTHFR activity, have been widely studied as potential markers of MTX toxicity and/or outcome in pediatric ALL. In this review, we show that the majority of published reports do not find association or present opposite effect. Therefore, MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL. The efforts should be focused on other genes, such as transporter genes or microRNA-related genes.

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“…The results indicate that monitoring the plasma concentration of MTX at 44 h is important for adjusting the dose of CF to decrease the MTX-related toxicities in the original treatment protocol of HD-MTX in all children with ALL. Interestingly, a recent study of HD-MTX treatment in children with ALL showed relationships between polymorphisms in folate-related genes and toxicities 28. However, routine monitoring of plasma concentration of MTX still has an important role in adjusting the dose of CF to decrease the MTX-related toxicities in practice before individual prediction of MTX-related toxicities based on pretreatment genotyping reach a practical use 26,29.…”

Section: Discussionmentioning

confidence: 99%

<p>Identifying risk factors for high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia</p>

Li¹,

Zhong-guo²,

Jing³

et al. 2019

CMAR

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Background Whether monitoring of the methotrexate (MTX) concentrations after high-dose MTX (HD-MTX) infusion can predict toxicities is still controversial, especially when HD-MTX therapy is used in the treatment of children with acute lymphoblastic leukemia (ALL), which is different than the previous schedules. The relationship between patient characteristics and severe adverse events (AEs) has yet to be determined. Objective To analyze the relationship between the MTX concentration and toxicities and to identify the risk predictors from patient characteristics for severe AEs during HD-MTX therapy in children with ALL. Methods We conducted a retrospective study on children with ALL who were treated with 388 HD-MTX infusions. The chi-square test and univariate and logistic regression analyses were used to analyze the relationship between the MTX concentrations and toxicities and to identify predictors for severe AEs. Results Febrile neutropenia ( P =0.000) and vomiting ( P =0.034) were more likely to occur if the infusion had an MTX level ≥1 μmol/L at 44 h, but other toxicities had no correlations with MTX concentration. Predictive factors for toxicities were as follows: higher risk stratification and higher values of albumin (ALB) for leucopenia, higher values of white blood cell count (WBC) for anemia, higher values of ALB and creatinine (Cr) for neutropenia, higher risk stratification and higher 44-h MTX concentration for febrile neutropenia, higher values of alanine transferase (ALT) for elevated ALT, higher values of ALT for elevated aspartate transferase (AST), and higher values of total bilirubin (TBil) for vomiting. Conclusion Routine monitoring of 44-h MTX concentrations is essential to identify patients at high risk of developing febrile neutropenia and vomiting. This study may provide a reference for clinicians to distinguish patients with a relatively high risk of severe AEs based on certain characteristics before HD-MTX infusion.

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Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia

Cited by 19 publications

References 36 publications

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

<p>Identifying risk factors for high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia</p>

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