Relationship between SLCO1B1 521T>C genovariation and severe toxicity during high-dose methotrexate chemotherapy

Abstract

Objective To investigate the relationship between severe toxicity during high-dose methotrexate (HD-MTX) chemotherapy and 29 related factors including SLCO1B1 521T>C genovariation, and to enhance drug safety. Methods Eighty-two children with acute lymphoblastic leukemia (ALL) received HD-MTX chemotherapy.The regimen was MTX 3-5 g/m2 continuous infusion for 24 hours.The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to detect the patients' genotypes of SLCO1B1 T521C polymorphism, which was the coding gene of organic anion transporting polypeptide 1B1 (OATP1B1). Haematological, gastrointestinal and hepatic toxicities in 1-10 days after HD-MTX administration were observed and graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 4.02). The patients were divided into two groups based on toxicity grades: case group (grades Ⅲ-Ⅴ) and normal group (grades 0-Ⅱ). The differences of 29 variates including biology features, biochemical indicators, SLCO1B1 T521C polymorphism and etc.were compared between the two groups by univariate analysis, and the significant factors were found out.The final predictive model of severe HD-MTX-related toxicity was set up through Logistic regression analysis.Receiver operating characteristic (ROC) curve of predictor was drawn based on final model in order to evaluate its predictive ability. Results There were only 4 significant different variates between case group and normal group (P C genovariation (odds ratio 18.489, 95% confidence interval 5.413-63.157) was the significant independent predictor for severe HD-MTX-related toxicity.The area under ROC (95% confidence interval) of SLCO1B1 521T>C genovariation as the predictor for severe HD-MTX-related toxicity was 0.776 (0.653-0.899), which had significant diagnositic value(P<0.05). Conclusions There is higher risk of severe HD-MTX-related toxicity while patients having SLCO1B1 521T>C genovariation.Clinician should consider it and take some protective measures. Key words: Acute lymphoblastic leukemia; Methotrexate; Severe toxicity; Organic anion transporting polypeptide; Gene polymorphism