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Dihydrofolate Reductase Genetic Polymorphisms Affect Methotrexate Dose Requirements in Pediatric Patients With Acute Lymphoblastic Leukemia on Maintenance Therapy

Gervasini, Guillermo PharmD, PhD*; de Murillo, Silvia G. PharmD*; Jiménez, Mercedes BSc*; de la Maya, María D. MD; Vagace, Jose M. MD, PhD

Journal of Pediatric Hematology/Oncology: November 2017 - Volume 39 - Issue 8 - p 589–595
doi: 10.1097/MPH.0000000000000908
Original Articles

We have aimed to determine the effect of polymorphisms in regulatory regions of the DHFR gene in relation to methotrexate (MTX) dose adjustments and drug-induced toxicity in children on maintenance therapy for acute lymphoblastic leukemia (ALL). In total, 41 children diagnosed with ALL were screened for 3 tag-single nucleotide polymorphisms in the DHFR promoter (C-1610G, C-680G/T, A-317G) and an intronic 19-bp insertion/deletion. Genotypes were analyzed in relation to dose requirements and toxicity. The percentage of MTX dose administered (with respect to protocol-recommended values) was affected by DHFR polymorphisms. Carriers of the −680AA genotype displayed a median percentage of 44.08 (interquartile range=34.69), compared with 77.98 (interquartile range=33.90) for CC and CA carriers (P=0.01). The number of counts within white blood cell therapeutic range (2.0 to 3.0×109/L) was higher for −680AA carriers than for CC/CA carriers (P=0.003). With regard to toxicity, carriers of the −680AA genotype displayed more treatment interruptions than CC/CG carriers (P=0.03), as well as more episodes of severe neutropenia (P=0.04) and higher number of blood counts with elevated levels (>400 mg/dL) of lactate dehidrogenase (P=0.04). Overall, our findings suggest that the identification of DHFR polymorphisms in the promoter region of the gene may be helpful in tailoring MTX doses for ALL pediatric patients on maintenance therapy.

*Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura

Service of Pediatric Hematology, Materno Infantil Hospital, Badajoz, Spain

Supported in part by grant PI15/00804 from Instituto de Salud Carlos III, Madrid, Spain and grant GR15012 from Junta de Extremadura, Consejeria de Economia, Comercio e Innovacion, Merida, Spain.

The authors declare no conflict of interest.

Reprints: Guillermo Gervasini, PharmD, PhD, Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, 06071, Badajoz, Spain (e-mail:

Received February 24, 2017

Accepted June 7, 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.