Abstract
Methotrexate (MTX) is a key agent for the treatment of childhood acute lymphoblastic leukemia (ALL). Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects. ATP-binding cassette subfamily C member 2 (ABCC2) is important for excretion of MTX and its toxic metabolite. The ABCC2 −24C>T polymorphism (rs717620) reportedly contributes to variability of MTX kinetics. In the present study, we assessed the association between the ABCC2 −24C>T polymorphism and methotrexate (MTX) toxicities in childhood ALL patients treated with high-dose MTX. A total of 112 Han Chinese ALL patients were treated with high-dose MTX according to the ALL-Berlin-Frankfurt-Muenster 2000 protocol. Our results showed that presence of the −24T allele in ABCC2 gene led to significantly higher MTX plasma concentrations at 48 hours after the start of infusion, which would strengthen over repeated MTX infusion. The −24T allele in ABCC2 gene was significantly associated with higher risks of high-grade hematologic (leucopenia, anemia, and thrombocytopenia) and non-hematologic (gastrointestinal and mucosal damage/oral mucositis) MTX toxicities. This study provides the first evidence that the −24T allele in ABCC2 gene is associated with the severity of MTX toxicities, which add fresh insights into clinical application of high-dose MTX and individualization of MTX treatment.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common malignant tumor in children
We explored effects of the ATP-binding cassette subfamily C member 2 (ABCC2) 224C.T polymorphism on MTX plasma concentrations in a relatively large childhood ALL patient population (n = 112) treated with high-dose MTX, and for the first time assessed the association between the ABCC2 224C.T polymorphism and MTX toxicities
The ABCC2 224C.T polymorphism reportedly contributes to variability of MTX kinetics [12]
Summary
The overall cure rate of ALL in children is about 80% [1]. Chemotherapy is a major element of the treatment for childhood ALL. Chemotherapy resistance is the major cause of treatment failure [1]. Methotrexate (MTX), a key agent for the treatment of childhood ALL, is a tight-binding inhibitor of the enzyme dihydrofolate reductase, which disrupts cellular folate metabolism [2]. High-dose MTX can significantly increase cure rates and improve patients’ prognosis [4]. Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects [3]. High-dose MTX requires pharmacokinetic monitoring to avoid significant toxicities [5], and the prediction of high-dose MTX toxicity is a key issue in individualization of treatment for childhood ALL [6]
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