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The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue

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Abstract

Purpose

In the last years, the influence of different genes involved in metabolism of chemotherapeutic agents has been studied. Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL) and Burkitt’s lymphomas (BL). This study aims to evaluate the role of MTHFR C677T and A1298C polymorphisms and G80A reduced folate carrier gene (RFC1) in a cohort of adult patients with lymphoproliferative malignancies submitted to high-dose MTX followed by leucovorin rescue.

Methods

We performed the analysis of these polymorphisms on genomic DNA with RFLP–PCR.

Results

Patients carrying MTHFR A1298C variant showed decreased hepatic and hematological toxicity (P = 0.03). Overall survival (OS) and progression-free survival (PFS) between homozygous wild-type and variant patients for the RFC1 G80A were significantly different (P = 0.035 and P = 0.02, respectively). A significant correlation between hematological toxicity and age (P = 0.003) was observed. There was no significant influence of MTHFR C677T genotype on toxicity, OS and PFS.

Conclusions

Leucovorin rescue given after high-dose MTX probably accounts for the lack of influence of C677T polymorphism. To better define a role of RFC1 polymorphism on patients outcome, it would be worthwhile to perform a study on intracellular MTX level and RFC1 substrate binding affinities in different genotypes.

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Acknowledgments

This work was supported by Fondi di Ricerca Linea D1 progetti di ricerca 2009.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Hematology, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy

    Patrizia Chiusolo, Sabrina Giammarco, Silvia Bellesi, Elisabetta Metafuni, Nicola Piccirillo, Daniela De Ritis, Sara Marietti, Sorà Federica, Luca Laurenti, Luana Fianchi, Stefan Hohaus, Leone Giuseppe & Simona Sica

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  1. Patrizia Chiusolo
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  2. Sabrina Giammarco
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  3. Silvia Bellesi
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Corresponding author

Correspondence to Patrizia Chiusolo.

Additional information

Patrizia Chiusolo and Sabrina Giammarco equally contributed to the study.

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Chiusolo, P., Giammarco, S., Bellesi, S. et al. The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue. Cancer Chemother Pharmacol 69, 691–696 (2012). https://doi.org/10.1007/s00280-011-1751-4

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