Influencia de los polimorfismos genéticos en la respuesta terapéutica a metotrexato de pacientes con neoplasias hematológicas

Resumen

Methotrexate (MTX) is the cornerstone of the protocols for the treatment of acute lymphoblastic leukemia (LAL), the most frequent malignancy in children. Despite the improvement in dosing regimens, there is still great variability in the therapeutic responses to the drug. The objective of this study was to determine how the presence of genetic polymorphisms in (i) the dihydrofolate reductase (DHFR) gene and (ii) in transporters involved in the bioavailability of MTX, affects the dosage, efficacy and toxicity of the drug in pediatric LAL patients undergoing maintenance chemotherapy. The results of the first part of our work indicate that patients carrying the DHFR -680AA genotype experienced more episodes of severe neutropenia and a greater number of controls with elevated LDH levels. In addition, this genotype was associated with a lower percentage of MTX administered with respect to standard doses, and with a greater number of blood controls with both low leukocytes and leukocytes in therapeutic range. In the second part of this study, we observed a marked effect of the ABCB1 C1236T polymorphism on the percentage of blood controls with effective myelosuppression and on the appearance of neutropenia. In addition, carriers of the homozygous ABCB1 1236TT genotype received a lower percentage of 6-MP dose than patients with the CC or CT genotypes. On the other hand, carriers of the ABCC4 934A genotype received an initial dose percentage of MTX higher than the standard in comparison with patients who did not present this variant. In conclusion, there are genetic variants in the genes analyzed that can affect both the efficacy and the toxicity of MTX. Their identification could help customize the doses administered in maintenance.