Effect of polymorphisms in transporter genes on dosing, efficacy and toxicity of maintenance therapy in children with acute lymphoblastic leukemia.

The aim of the present work was to assess whether polymorphisms in genes coding for drug transport proteins may influence dosing, efficacy and toxicity of maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6MP) in childhood acute lymphoblastic leukemia (ALL). A total of 41 children with ALL were screened for 10 SNPs in the SLC19A1, ABCB1, ABCC2, ABCC4 and ABCG2 transporter genes by means of direct sequencing. Carriers of the ABCC4 934CC and ABCB1 1236TT genotypes received a lower percentage of the protocol-recommended starting dose of MTX (62.1 vs. 81.3% for 934CA carriers, p=0.001) and 6MP (73.1 vs. 87.7% for 1236CC/CT carriers; p=0.026), respectively. The C1236T SNP also increased the efficiency of myelosuppression. Median (and interquartile) number of blood tests with leukocytes levels <3109/L for the CC; CT and TT genotypes were 22 (13), 30.5 (11.75) and 33 (17.25), respectively (p=0.001). In addition, this SNP also correlated with the number of hematological adverse events (p=0.004 for the difference between same genotypes). The event more profoundly affected was neutropenia (p=0.004). In the same manner, the ABCC4 934CC genotype was also associated to more frequent hematological toxicity (p=0.041 vs. CT carriers) and raised LDH levels (p=0.004 vs. CT carriers); although only the latter association remained significant after correction by multiple testing. Overall, our findings indicate that variability in the ABCB1 and ABCC4 genes may confer higher sensitivity to maintenance chemotherapy of ALL, and therefore its determination may be helpful in individualizing this treatment.

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 3.0×10/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.