Published online 31 July 2009
Haematologica, Vol 94, Issue 10, 1391-1398 doi:10.3324/haematol.2009.008326
Copyright © 2009 by Ferrata Storti Foundation
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Acute Lymphoblastic Leukemia

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

Alessia Ongaro1, Monica De Mattei1, Matteo Giovanni Della Porta2, GianMatteo Rigolin3, Cristina Ambrosio3, Francesco Di Raimondo4, Agnese Pellati1, Federica Francesca Masieri1, Angelo Caruso1, Linda Catozzi5, Donato Gemmati5

1 Department of Morphology and Embryology, Section of Histology, University of Ferrara
2 Department of Hematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
3 Department of Biomedical Sciences and Advanced Therapies, Section of Hematology, University of Ferrara
4 Department of Biomedical Sciences, Section of Hematology, University of Catania
5 Department of Biomedical Sciences and Advanced Therapies, Section of Haematology, Center for the Study of Hemostasis and Thrombosis, University of Ferrara, Italy

Correspondence: Monica De Mattei/Alessia Ongaro, Department of Morphology and Embryology, Section of Histology, University of Ferrara, Via Fossato di Mortara 64/B, 44100 Ferrara, Italy. E-mail:dmm{at}unife.it/ngrlss{at}unife.it

Background: The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates.

Design and Methods: The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia.

Results: Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45).

Conclusions: Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival.

Key words: gene polymorphisms, adult acute lymphoblastic leukemia, methotrexate-related toxicity, folate.