Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia

Background: Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of antileukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercap-topurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to ALL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercap-topurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6-mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto-purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (AUC=0.71). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurine-induced toxicity in pediatric ALL.