Clinical Implications of Methotrexate Pharmacogenetics in Childhood Acute Lymphoblastic Leukaemia

Gervasini, Guillermo; Mota-Zamorano, Sonia

doi:10.2174/1389200220666190130161758

Cited by 20 publications

(21 citation statements)

References 165 publications

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“…High-dose methotrexate (HDMTX) is commonly defined as an intravenous dose greater than 500 mg/m 2 (Howard et al, 2016), and HDMTX is recommended as an essential component of chemotherapy for ALL and non-Hodgkin lymphoma (NHL) in clinical guidelines (National Comprehensive Cancer Network, 2021a;. Although breakthroughs have been made in the complex treatment of hematological malignancies, HDMTX still plays a key role and is established as the first-line drug (Gervasini and Mota-Zamorano, 2019). However, patients differ largely in their response to treatment regarding HDMTX pharmacokinetics and toxicities, even when given the identical dose (Schmiegelow, 2009;Giletti and Esperon, 2018).…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…It has been revealed that the increase of dihydrofolate reductase and the damage of MTX transport are key factors in MTX resistance in childhood ALL (41). Previous studies have measured the difference in MTX resistance-related mRNA expression levels in childhood leukaemia by standardized RT-qPCR based on a competitive template, and observed that in T-ALL, compared with ordinary/pre-B-ALL, the difference in MTX resistance, dihydrofolate reductase (DHFR), thymidylate synthetase (TS) and folylpolyglutamate synthase mRNA expression levels are increased (22,42,43). The present results suggested that HSH2D is one of the important factors affecting MTX resistance, and identified via gene manipulation that HSH2D expression is necessary for HuT-78 cells resistance to MTX.…”

Section: Discussionmentioning

confidence: 99%

HSH2D contributes to methotrexate resistance in�human T‑cell acute lymphoblastic leukaemia

Wang

Xiong

2020

Oncol Rep

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Acute lymphoblastic leukaemia (ALL) is a malignant proliferative disease that originates from B-lineage or T-lineage lymphoid progenitor cells. Resistance to chemotherapy remains an important factor for treatment failure. The aim of the present study was to investigate drug resistance in T-cell ALL (T-ALL). Bioinformatics analysis of Oncomine and Gene Expression Omnibus data was performed to evaluate the expression of haematopoietic SH2 domain containing (HSH2D) in various lymphomas. HuT-78 cells with HSH2D overexpression and or knockdown were constructed, and the effect on related downstream signalling molecules was detected. To study the effect of HSH2D on methotrexate (MTX) resistance, cell cycle and apoptosis analyses were conducted using flow cytometry, and MTT and EdU assays were used to detect the effect of MTX resistance and HSH2D gene expression on the biological function of HuT-78 cells. Via the analysis of the data sets, it was identified that the expression of HSH2D was downregulated in TALL compared with B-cell ALL. Western blotting and reverse transcription-quantitative PCR demonstrated that the overexpression of HSH2 resulted in the inhibition of CD28-mediated IL-2 activation. In related experiments with drug-resistant cell lines, it was determined that HSH2D expression is necessary for HuT-78 cells to be resistant to MTX. In conclusion, the results suggested that HSH2D serves an important role in the resistance of TALL to MTX, which provides a potential research target for the study of drug resistance of TALL .

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“…Современные исследования позволили сделать вывод о том, что одной из важнейших причин индивидуальных различий в фармакологическом ответе на лечение МТХ являются генетические особенности пациентов, определяющие до 50 % всех атипичных реакций. Согласно полученным данным, среди факторов, влияющих на терапевтический эффект и безопасность МТХ, большая роль отводится однонуклеотидным полиморфизмам в генах, определяющим индивидуальные особенности ФК МТХ [14][15][16].…”

Section: метотрексатunclassified

“…Наличие SNP rs639174 в гене DROSHA связано с гастроинтестинальной токсичностью, индуцированной МТХ у детей с B-линейным ОЛЛ. Это исследование впервые продемонстрировало потенциальную роль полиморфизмов в генах процессинга miRNA для прогнозирования токсичности при лечении ОЛЛ [16,20]. Дальнейшие исследования miRNA, эпигенетики и полногеномного секвенирования смогут прояснить индивидуальную вариабельность эффективности и токсичности МТХ.…”

Section: метотрексатunclassified

“…Тогда как в других работах авторы установили высокую индивидуальную вариабельность уровней 6-ТГ и выявили корреляцию с рецидивом. Следовательно, необходимо минимизировать колебания дозировки 6-МР на этапе поддерживающей терапии в целях снижения риска рецидива заболевания [16,32,33].…”

Section: о б з о р ы л и т е р а т у р ы || L I T E R a T U R E R E V I E Wunclassified

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A review of pharmacogenetic aspects of methotrexate and 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia treatment

Гурьева

Савельева

Валиев

2021

Ross. ž. det. gematol. onkol.

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Significant progress in the treatment of acute lymphoblastic leukemia (ALL) in children has resulted from the development of effective chemoand supportive care therapy protocols. The vector of further research is aimed at reducing toxicity and long-term side effects. The study of pharmacogenetic aspects of toxicity of the main drugs used in the treatment of ALL – methotrexate and 6-mercaptopurine – allowed to identify oligonucleotide polymorphisms that correlate with the concentration of the drug in blood, toxic effects and the risk of relapse of ALL. The clinical administration of pharmacogenetic methods remains a challenging task, requiring additional research, which will make it possible to individualize the ALL therapy on the basis of the results of molecular profiling.

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Clinical Implications of Methotrexate Pharmacogenetics in Childhood Acute Lymphoblastic Leukaemia

Cited by 20 publications

References 165 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

HSH2D contributes to methotrexate resistance in�human T‑cell acute lymphoblastic leukaemia

A review of pharmacogenetic aspects of methotrexate and 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia treatment

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