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

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 3.0x10(9)/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.