UGT1A1 gene polymorphism and frequency of hyperbilirubinemia in chronic myeloid leukemia patients treated by nilotinib

Background. Polymorphisms in the UGT1A1 gene (especially the homozygous (TA)(7)/(TA)(7)genotype), which encodes the uridine diphosphate glucuronyltransferase 1 (UDP-GT) enzyme in hepatocytes, may manifest with isolated indirect hyperbilirubinemia. Hyperbilirubinemia is also most common laboratory abnormality in chronic myeloid leukemia (CML) patients treated by nilotinib. Aim. To estimate the correlation between of UGT1A 1 gene polymorphism and frequency of hyperbilirubinemia in CML patients treated by nilotinib. Materials and methods. Our study included 100 CML patients treated by nilotinib. We analyzed their blood bio-chemistry, namely the level of bilirubin, the activity of liver enzymes (AST and ALT), the time to development of hyperbilirubinemia, and the time until normalization of blood biochemistry. We also studied the promoter region of the UGT1A1 gene in these patients with allele-specific polymerase chain reaction (AS-PCR). Results. Indirect hyperbilirubinemia was observed in 84 (84%) of 100 patients. Of those, 41 (49%) had grade 1 hyperbilirubinemia, 33 (39%) had grade 2 hyperbiliru-binemia, and 10 (12%) had grade 3 hyperbilirubinemia. Normal genotype (TA)(6)/(TA)(6) was found in 71 (71%) patients, 19 (19%) patients had a heterozygous (TA)(6)/(TA)(7) genotype, and 10 (10%) patients had a homozygous (TA)(7)/(TA)(7) genotype. Eight of the 84 CML patients with hyperbilirubinemia (9,5%) had a transient elevation of ALT and AST: grade 1 in 1 case, grade 2 in 5 cases, and grade 3-4 in 2 cases. Conclusion. In CML patients treated with nilotinib, grade 3 hyperbilirubinemia may be a sign of (TA)(7)/(TA)(7) polymorphism in promoter region of the UGT1A1 gene. Low-grade hyperbilirubinemia occurs both in patients with normal UGT1A1 genotype and in patients heterozygous for the (TA), polymorphism. No connection between UGT1A1 polymorphisms and elevated liver enzymes (ALT, AST) was established.