Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma

Kotnik, Barbara Faganel; Grabnar, Iztok; Grabar, Petra Bohanec; Dolžan, Vita; Jazbec, Janez

doi:10.1007/s00228-011-1046-z

Cited by 90 publications

(80 citation statements)

References 46 publications

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“…In concordance with our previous studies, investigating HD-MTX pharmacokinetics3 and HDMTX-related toxicity in children with ALL4, we observed significantly higher AUC levels in carriers of at least one MTHFR 677T allele compared to patients with wild-type genotype. Similar to our findings, other studies also reported the influence of MTHFR 677T allele on higher MTX plasma levels 7,8.…”

Section: Discussionsupporting

confidence: 92%

“…Only patients with lymphoblastic T-cell NHL treated according to the BFM protocols3 who received HD-MTX during consolidation phase were included into the study group. Toxicity evaluation and HD-MTX pharmacokinetics data collection and analysis were described previously 4.…”

Section: Methodsmentioning

confidence: 99%

“…The imbalance of folate homeostasis may lead to DNA synthesis arrest and could disrupt DNA and protein methylation reaction. Our previous studies showed that genetic variability in the key folate pathway enzymes, 5,10-methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), 5,10-methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TYMS), might influence MTX pharmacokinetics and treatment outcome in children with ALL 3,4. Therefore, the aim of the present study was to assess the influence of polymorphisms in these genes on HDMTX-related toxicity in children with NHL treated according to Berlin-Frankfurt-Münster (BFM) protocols.…”

Section: Introductionmentioning

confidence: 99%

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The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

Erčulj

Kotnik

Debeljak

et al. 2014

Radiology and Oncology

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BackgroundWe evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL).Patients and methodsIn total, 30 NHL patients were genotyped for selected folate pathway polymorphisms.ResultsCarriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype.ConclusionsOur results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTX-related toxicity in children with NHL.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

Erčulj

Kotnik

Debeljak

et al. 2014

Radiology and Oncology

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“…The effect of MTHFR polymorphisms in mediating this risk again show mixed results, being confirmed by multiple high level studies [26,[67][68][69], yet having no association found in other studies [97]. Multiple SNPs in SLCO1B1, an MTX transporter gene; efflux transporter genes ABCB1, ABCC4; as well as genes otherwise involved in folate metabolism such as GSTM1 and GSTT1 have been variably linked with MTX plasma levels, hepatotoxicity, and the occurrence of mucositis [30, 46, 56-61, 98, 99].…”

Section: Gastrointestinal Toxicitymentioning

confidence: 89%

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Maxwell

Cole

2017

Curr Hematol Malig Rep

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Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

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“…The present case developed toxicity despite the rescue, the probable factors to be considered are high dosage with respect to her body weight, not recognising the minor side effects initially and not advocating the double dose of leucovorin inspite of the advice and may be due to hypersensitivity to methotrexate because of MTHFR 2 mutations 11. The other reasons for methotrexate toxicity reported in the literature include genetic polymorphism in the folate metabolic pathway delaying the clearance of methotrexate,12 delay in renal excretion due to consumption of cola beverages,13 the state of hydration, concomitant drugs taken such as trimethoprim and sulphamethoxazole, and proton pump inhibitor like dilantin 14. Methotrexate clearance was moderately reduced in patients with the MTHFR 677TT.…”

Section: Discussionmentioning

confidence: 99%

Life-threatening complications following multidose methotrexate for medical management of ectopic pregnancy

Dasari

Sagili

2012

BMJ Case Reports

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SummaryA 25-year-old primigravida was diagnosed to be suffering from unruptured ectopic pregnancy. The serum β-human chorionic gonadotropin levels were 2851 mIU/l and the ectopic gestational sac was 2.7×2.7 cm without any fetal pole. It was decided to manage her by expectant therapy. But she received medical therapy with multidose methotrexate because of misinterpretation of expectant therapy as medical therapy. She suffered from methotrexate toxicity, which manifested as high-grade fever, vomiting, melena, oral ulcerations, pneumonitis, subconjunctival haemorrhages and skin pigmentation. She developed severe third space fluid collection and shock, which was mistaken for rupture ectopic gestation. Her haematological picture showed severe neutropaenia and thrombocytopaenia which confirmed the clinical picture to be due to methotrexate toxicity. She also developed septicaemia and candidal infection secondary to immunosuppression. She was managed in intensive care unit with ventilatory support, high-dose leucovorin and injection filgastrim. She responded well to the therapy with dramatic recovery in 4 days. BACKGROUND

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Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma

Cited by 90 publications

References 46 publications

The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Life-threatening complications following multidose methotrexate for medical management of ectopic pregnancy

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