Advances in Clinical and Experimental Medicine
2018, vol. 27, nr 8, August, p. 1061–1068
Publication type: original article
Use of MTHFR C677T polymorphism and plasma pharmacokinetics to predict methotrexate toxicity in patients with acute lymphoblastic leukemia
1 Department of Pharmacology, Faculty of Medicine, University of Sfax, Tunisia
2 Department of Hematology, Hedi Chaker University Hospital, Sfax, Tunisia
3 Department of Histology, Faculty of Medicine, University of Sfax, Tunisia
Background. Methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy, but it is associated with serious toxicities in a considerable number of patients.
Objectives. The aim of the current study was to determine which variables were associated with MTX toxicity in children, adolescents and young adults with ALL.
Material and Methods. In this prospective study, 35 patients with newly diagnosed ALL, treated according to the 58951 European Organization for Research and Treatment of Cancer – Children’s Leukemia Group (EORTC-CLG) protocol, were prospectively enrolled. Toxicity data was collected objectively after each high-dose methotrexate (HD-MTX) course. The risk factors of MTX toxicity were determined using multiple linear regression analysis, with age, gender, immunophenotype, risk group, plasma MTX levels, plasma homocysteine (HCY) levels, and MTHFR C677T included as independent variables.
Results. Twenty-five (71.4%) patients experienced toxicity on at least 1 course of HD-MTX. In the univariate linear regression, the global toxicity score was associated with a significant rise in plasma HCY concentrations within 48 h after MTX administration (β = 0.4; R2 = 0.12; p = 0.02). In the multiple regression model, the global toxicity score was significantly associated with a higher MTX plasma levels at 48 h (β = 0.5; R2 = 0.38; p = 0.001) and CT 677 MTHFR genotype (β = 0.3; R2 = 0.38; p = 0.01).
Conclusion. Routine monitoring of plasma MTX concentrations is essential to detect patients at a high risk of MTX toxicity. MTHFR C677T genotyping may be useful for predicting MTX toxicity.
methotrexate, acute lymphoblastic leukemia, MTHFR C677T polymorphism, toxicity
- Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354:166–178.
- Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350:1535–1548.
- de Beaumais TA, Jacqz-Aigrain E. Intracellular disposition of methotrexate in acute lymphoblastic leukemia in children. Curr Drug Metab. 2012;13:822–834.
- Assaraf YG. Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007;26:153–181.
- Mikkelsen TS, Thorn CF, Yang JJ, et al. PharmGKB summary: Methotrexate pathway. Pharmacogenet Genomics. 2011;21:679–686.
- Bagley PJ, Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci USA. 1998;95:13217–13220.
- Ongaro A, De Mattei M, Della Porta MG, et al. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: Effects on methotrexate-related toxicity and survival. Haematologica. 2009;94:1391–1398.
- Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem. 1996;42:1322–1329.
- Tantawy AA, El-Bostany EA, Adly AA, et al. Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis. 2010;21:28–34.
- Vilmer E, Suciu S, Ferster A, et al.; Children Leukemia Cooperative Group. Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: A CLCG-EORTC report. Leukemia. 2000;14:2257–2266.
- De Moerloose B, Suciu S, Bertrand Y, et al. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): Report of the EORTC randomized phase 3 trial 58951. Blood. 2010;116:36–44.
- Domenech C, Suciu S, De Moerloose B, et al. Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014;99:1220–1227.
- Nirenberg A, Mosende C, Mehta BM, Gisolfi AL, Rosen G. High-dose methotrexate with citrovorum factor rescue: Predictive value of serum methotrexate concentrations and corrective measures to avert toxicity. Cancer Treat Rep. 1977;61:779–783.
- Paci A, Veal G, Bardin C, et al. Review of therapeutic drug monitoring of anticancer drugs. Part 1: Cytotoxics. Eur J Cancer. 2014;50:2010–2019.
- Ayad MW, El Naggar AA, El Naggar M. MTHFR C677T polymorphism: Association with lymphoid neoplasm and effect on methotrexate therapy. Eur J Haematol. 2014;93:63–69.
- National Institutes of Health. National Cancer Institute CTEP CTCAE v. 5.0. 2016. http://ctep.cancer.gov/. Accessed November 27, 2017.
- Radtke S, Zolk O, Renner B, et al. Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood. 2013;121:5145–5153.
- Schmiegelow K. Advances in individual prediction of methotrexate toxicity: A review. Br J Haematol. 2009;146:489–503.
- Holmboe L, Andersen AM, Mørkrid L, Slørdal L, Hall KS. High dose methotrexate chemotherapy: Pharmacokinetics, folate and toxicity in osteosarcoma patients. Br J Clin Pharmacol. 2012;73:106–114.
- Sonis ST. Mucositis as a biological process: A new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol. 1998;34:39–43.
- Sonis ST, Elting LS, Keefe D, et al.; Mucositis Study Section of the Multinational Association for Supportive Care in Cancer, International Society for Oral Oncology. Perspectives on cancer therapy-induced mucosal injury: Pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100:1995–2025.
- Pico JL, Avila-Garavito A, Naccache P. Mucositis: Its occurrence, consequences, and treatment in the oncology setting. Oncologist. 1998;3: 446–451.
- Rask C, Albertioni F, Bentzen SM, Schroeder H, Peterson C. Clinical and pharmacokinetic risk factors for high-dose methotrexate-induced toxicity in children with acute lymphoblastic leukemia − a logistic regression analysis. Acta Oncol. 1998;37:277–284.
- Relling MV, Fairclough D, Ayers D, et al. Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol. 1994;12:1667–1672.
- Cheng KK. Association of plasma methotrexate, neutropenia, hepatic dysfunction, nausea/vomiting and oral mucositis in children with cancer. Eur J Cancer Care (Engl). 2008;17:306–311.
- Cole PD, Beckwith KA, Vijayanathan V, Roychowdhury S, Smith AK, Kamen BA. Folate homeostasis in cerebrospinal fluid during therapy for acute lymphoblastic leukemia. Pediatr Neurol. 2009;40:34–41.
- Valik D, Radina M, Sterba J, Vojtesek B. Homocysteine: Exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy. Pharmacogenomics. 2004;5:1151–1162.
- Kubota M, Nakata R, Adachi S, et al. Plasma homocysteine, methionine and S-adenosylhomocysteine levels following high-dose methotrexate treatment in pediatric patients with acute lymphoblastic leukemia or Burkitt lymphoma: Association with hepatotoxicity. Leuk Lymphoma. 2014;55:1591–1595.
- Tufekci O, Yilmaz S, Karapinar TH, et al. A rare complication of intrathecal methotrexate in a child with acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2011;28:517–522.
- Seshadri S, Wolf PA, Beiser AS, et al. Association of plasma total homocysteine levels with subclinical brain injury: Cerebral volumes, white matter hyperintensity, and silent brain infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study. Arch Neurol. 2008;65:642–649.
- Bottiglieri T. Homocysteine and folate metabolism in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1103–1112.
- Haagsma CJ, Blom HJ, van Riel PL, et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis. 1999;58:79–84.
- Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: A review of molecular mechanisms and the evidence for folate’s role. Adv Nutr. 2012;3:21–38.
- Ientile R, Curro’ M, Ferlazzo N, Condello S, Caccamo D, Pisani F. Homocysteine, vitamin determinants and neurological diseases. Front Biosci (Schol Ed). 2010;2:359–372.
- Papatheodorou L, Weiss N. Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Signal. 2007;9:1941–1958.
- Goyette P, Sumner JS, Milos R, et al. Human methylenetetrahydrofolate reductase: Isolation of cDNA, mapping and mutation identification. Nat Genet. 1994;7:195–200.
- Kim YI. Folate and carcinogenesis: Evidence, mechanisms, and implications. J Nutr Biochem. 1999;10:66–88.
- Yamada K, Chen Z, Rozen R, Matthews RG. Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci USA. 2001;98:14853–14858.
- Robien K, Ulrich CM. 5,10-methylenetetrahydrofolate reductase polymorphisms and leukemia risk: A HuGE minireview. Am J Epidemiol. 2003;157:571–582.
- Fisher MC, Cronstein BN. Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol. 2009;36:539–545.
- Yang L, Hu X, Xu L. Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: A meta-analysis. Tumour Biol. 2012; 33:1445–1454.