How UGT1A1 genotype impacts on TKI efficacy and safety in chronic myeloid leukemia patients

Gilbert syndrome (GS) is a benign condition, characterized by intermittent unconjugated hyperbilirubinemia without structural liver damage, affecting about 10% of the white population. It is associated with variations in uridine-50 -diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1). GS can affect pharmacokinetic properties of tyrosine-kinase inhibitors (TKIs), which are currently used for the treatment of chronic myeloid leukemia (CML). In particular, the A(TA)7TAA polymorphism has been associated with nilotinib-induced hyperbilirubinemia in CML patients. The aim of this study was then to assess if in CML-chronic phase patients treated with either first, second or third-generation TKIs, GS had an impact on clinical outcomes as cytogenetic/molecular response rates and progression-free survival, as well as on hematological or extra-hematological toxicity. We retrospectively evaluated 105 CML patients (M/F = 61/44) treated with TKIs at our Institution. Median age at diagnosis was 51.4 years (range, 22.6-90.2). We performed PCR to identify variations in dinucleotide repeats in the UGT1A1 promoter region. Genotypes were assigned as follows: 6/6 [homozygous for (TA)6 allele] wild-type, 7/7 [homozygous for mutated (TA)7 allele] and 6/7 (heterozygous). Homozygous (TA)7 genotype was reported in 17 (16.2%) patients, 44 (41.9%) were heterozygous (TA)7 and the remaining wild-type. Concerning baseline characteristics, concomitant drugs were reported in 49 patients (46.7%), with 7 patients taking more than 5 medications. Efficacy and safety data are reported in Table 1. Comparing patients with or without GS, no difference was observed in the achievement of CCyR, MMR, DMR, hematological and extra-hematological toxicity, regardless of the TKI used. As expected, in homozygous (TA)7 patients a major rate of grade 3/4 hyperbilirubinemia was reported, without any difference from the TKI used. In clinical practice, GS is often underestimated, mainly because the specific text is performed only when bilirubin levels are significantly increased. However, it can be present also in patients with normal or borderline bilirubin levels. Interestingly, in our series GS has been detected in a higher percentage than expected (about 16.2% with homozygous genotype). In this study, even if homozygous patients showed a higher rate of grade 3/4 hyperbilirubinemia, GS did not seem to have a clinical impact on response rate and outcome in CML patients, regardless of the specific TKI used.