UGT1A1 genotype does not affect tyrosine kinase inhibitors efficacy and safety in chronic myeloid leukemia

To the Editor: Gilbert's syndrome (GS) is a condition characterized by intermittent unconjugated hyperbilirubinemia without structural liver damage, affecting about 10% of the caucasian population. It is an autosomal recessive disorder, mainly associated with variations in uridine50-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1). In Caucasians, the most common variation is the TATA box polymorphism, in which an insertion of an additional TA-repeat into the promoter region of the gene results in a A(TA) 7TAA sequence, that differs from the more prevalent A(TA) 6TAA. Gilbert's syndrome is a benign condition which does not lead to liver inflammation, cellular destruction, fibrosis, or cirrhosis but is merely clinically characterized by intermittent episodes of uncomplicated unconjugated hyperbilirubinemia. The effect of GS on liver complication and outcome of hematological malignancies has been scarcely investigated, with only a previous study in a series of children diagnosed with acute lymphoblastic leukemia, a series of adult patients with Hodgkin lymphoma and some anecdotal case reports in acute leukemia patients. Tyrosine-kinase inhibitors (TKIs) are currently used for the treatment of chronic myeloid leukemia (CML). Nilotinib inhibits bilirubin metabolism via UGT1A1, thereby increasing bilirubin levels; not surprisingly, GS has been associated with nilotinib-induced hyperbilirubinemia in patients affected by CML. Similar increases in bilirubin were also reported in patients with GS treated with imatinib or dasatinib. The aim of the present study is to assess if in CML-chronic phase (CML-CP) patients treated with either firstor second-generation TKIs, GS has an impact on clinical outcomes, assessed by cytogenetic/molecular response rates and progression-free survival (PFS), as well as on hematological or extra-hematological toxicities. We retrospectively collected data on CML-CP patients consecutively treated with TKIs at our institution between February 2002 and November 2018. All the following data were collected at baseline before TKI initiation: sociodemographic and hematological variables, disease risk scores (Sokal, Eutos, Hasford, and ELTS), and TKI starting dose. Monitoring and responses evaluation followed the current European LeukemiaNet recommendations. Progression-free survival was calculated from the start of first-line TKI to any of the following events: primary or secondary resistance, and/or discontinuation due to intolerance. Hematological and extra-hematological toxicities were graded according to the Common Toxicity Criteria Adverse Events (CTCAE) version 5.0. Gilbert's syndrome genotype was investigated by polymerase chain reaction (PCR) amplification of a region encompassing the TATA-box of the UGT1A1 gene (forward primer: 5’-GTC ACG TGA CAC AGT CAA AC-30: reverse primer: 50-TTT GCT CCT GCC AGA GGT-30; annealing temperature: 62°C. RefSeq UGT1A1 NG_033238.1). DNA fragment length analysiswas performed by 12%polyacrylamide gel electrophoresis (PAGE): a 98 bp fragment indicating the presence of the (TA)6TAA wildtype allele, while a 100 bp fragment accounts for the (TA)7TAA allele (c.-41_-40dupTA). The more rare (TA)8TAA allele (c.-43_-40dupTATA) could be as well evidenced by this technique as a 102 bp PCR product, but it was not detected in any of the patient studied. Clinical and sociodemographic characteristics were described using absolute and relative frequencies. We evaluated time to resistance (truncated at 10 years) according to GS genotype by calculating the Kaplan-Meier function and by fitting univariate and multivariable Cox models adjusted for gender, age, and line of therapy. P values were obtained from post-estimation global Wald tests. Statistical analysis was performed with Stata 15 (StataCorp. 2017). One hundred and five CML-CP patients consecutively treated with either firstor second-generation TKIs were evaluated. Clinicaldemographic data at diagnosis are showed in Table S1. In particular, concomitant drugs were reported in 49 patients (46.7%), with seven patients taking more than five medications. Gilbert's syndrome genotypes were distributed as follows: 17 (16.2%) patients were 7/7, 44 (41.9%) 6/7 and the remaining cases were wild-type. The majority of the patients were treated with imatinib (69.5%), following by nilotinib (17.1%) and dasatinib (13.3%). Complete cytogenetic response (CCyR) was obtained in 79 (75.2%) patients, of whom 55 (52.4%) were within 3 months of treatment. Among 7/7, 6/7 and 6/6 genotypes, CCyR was achieved by 12 (70.6%), 31 (70.4%) and 29 (65.9%) patients, respectively. Major molecular response (MMR) was obtained in 73 patients (69.5%); among them eight (47%) were 7/7, 23 (52.3%) 6/7 and 20 (45.4%) 6/6. Deep molecular response (DMR) was achieved in 51 (48.6%) patients, of whom 8 (47.1%), 23 (52.3%) and 20 (45.4%) showed a 7/7, 6/7, or 6/6 genotype, respectively. Interestingly, none of these differences was statistically significant. Forty-seven patients switched to second-line therapy, of whom 18 (38.3%) for primary resistance, 14 (29.8%) for secondary resistance and 15 (14.3%) for intolerance or unacceptable toxicity. Among patients who experienced primary resistance, two (22.2%) were 7/7, seven (36.8%) were 6/7 and nine (45%) wild-type. A similar distribution was also recorded among patients who switched for toxicity. Received: 4 July 2019 Revised: 23 July 2019 Accepted: 24 July 2019