Pharmacogenetic studies in children with acute lymphoblastic leukemia in Argentina

Abstract

The aim of this study was to evaluate the influence of the most common genetic variants in methylenetetrahydrofolate reductase (MTHFR), thiopurine methyltransferase (TPMT) and glutathione-S-transferases (GSTs) on the outcome of acute lymphoblastic leukemia (ALL) treatment in Argentinean children. Two hundred and eighty-six patients with ALL treated with two Berlin–Frankfurt–Münster (BFM)-based protocols were analyzed. Ten genetic variants were studied. Toxicity was evaluated during the consolidation phase. Children who received 2 g/m²/day of methotrexate and carried at least one 677T allele in MTHFR showed an increased risk of developing severe leukopenia (p = 0.004) and neutropenia (p = 0.003). Intermediate-risk (IR) patients with a heterozygous TPMT genotype had a higher probability of event-free survival than those with a wild-type genotype. Genotyping of MTHFR polymorphisms might be useful to optimize consolidation therapy, reducing the associated severe hematologic toxicity. Further studies are necessary to establish the usefulness of MTHFR and TPMT variants as additional markers to predict outcome in the IR group.

Keywords::

• ALL
• TPMT
• MTHFR
• GSTs
• pharmacogenetics
• pediatrics

Acknowledgements

We thank the patients and their parents for their participation in the project. We are grateful to Susana Rodriguez, MD, MSc, Carolina Cernadas, MD, MSc and Carlos Rocco, MSc for statistical analysis support. We also thank Dr. Jorge Rossi and Dr. Andrea Bernasconi for their collaboration in flow cytometry and index DNA determinations.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This work was partially supported by a research grant from the Consejo Nacional de Investigaciones Cientificas y Técnicas (CONICET) and the Roemmers Foundation.

Dr. Lilien Chertkoff is a member of the Carrera del Investigador Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).