Contribution of UGT1A1 variations to chemotherapy-induced unconjugated hyperbilirubinemia in pediatric leukemia patients

Abstract

Background: Chemotherapy for malignant neoplasms sometimes induces unconjugated hyperbilirubinemia, resulting in the early cessation of treatment. We evaluated the role of variations in the bilirubin uridine-5-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1) in unconjugated hyperbilirubinemia development during chemotherapy in pediatric patients with leukemia. Methods: UGT1A1 allelic variations were evaluated in 25 Japanese pediatric leukemia patients with hyperbilirubinemia (peak serum bilirubin concentration 3.57 ± 1.02 mg/dl) and 25 control patients without hyperbilirubinemia (0.92 ± 0.32 mg/dl) by PCR-direct sequencing. results: In the hyperbilirubinemic group, 22 of 25 patients showed biallelic variations of UGT1A1. Nine (36%) patients were homozygous for UGT1A1*6 and eight (32%) were compound heterozygous for UGT1A1*6 and UGT1A1*28. Three (12%) patients were homozygous for UGT1A1*28. There were no biallelic variations in UGT1A1 in the non-hyperbilirubinemic group. The allelic frequencies of UGT1A1*6 in the hyperbilirubinemic group (0.58) was significantly higher than those of the non-hyperbilirubinemic group (0.1) (χ 2 = 25.7, P < 0.05). conclusion: The high frequency of biallelic variations of UGT1A1 in the hyperbilirubinemic group suggests an association with Gilbert syndrome. Therefore, it is not necessary to cease chemotherapy in patients with these mutations who develop unconjugated hyperbilirubinemia without associated liver dysfunction.

Gilbert's Syndrome, Bilirubin Level and UGT1A1∗28 Genotype in Men of North-West Region of Russia

“…Unfortunately there are very few data on the population genetic characteristics of UGT1A1 in Russian residents. 18,19 Considering the high frequency of UGT1A1 biallelic variations and, first of all, homozygous variant UGT1A1*28 associated with unconjugated hyperbilirubinemia as a GS risk marker 15,20 we conducted this study to test this poly-morphism in 124 patients with a clinically confirmed diagnosis of GS and 74 healthy men in the North-West region of Russia to describe the prevalence of the UGT1A1*28 allele (genetic variant code is rs8175347) in these groups and in order to assess the clinical significance of such genetic testing for people with hyperbilirubinemia. Therefore the genetic testing data were compared with the serum bilirubin level values for each project participant.…”

“…36 In particular, the UGT1A1 *28 polymorphism increases the likelihood of adverse side reactions when using a number of antineoplastic agents. 37 Chemotherapy of malignant neoplasms using irinotecan, sorafenib, 20,21,38 and belinostat 39 is accompanied by a significant increase in the toxicity of these drugs in patients with GS primarily increasing unconjugated hyperbilirubinemia. That often leads to premature termination of treatment.…”

“…That often leads to premature termination of treatment. 20,21,40 In addition, patients with UGT1A1 *28 treated with irinotecan have an increased risk of diarrhea and neutropenia. 41,42 It is obvious that empirical dose adjustment is necessary when using chemotherapy for patients with GS.…”

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

“…1 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, 2 a series of adult patients with Hodgkin lymphoma 3 and some anecdotal case reports in acute leukemia patients. 4 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.…”

“…Revised (R) in 2012,3 this score includes bone marrow blast percentage, hemoglobin level, absolute neutrophil count, platelet count and cytogenetics. There is no definite prognostic impact from Idic(X)(q13), and is considered as another abnormality in the intermediate group of the IPSS-R.Recently, exome and genome-wide sequencing of MDS cases revealed a great diversity of genomic aberrations, with more than 25 recurrent mutations 4. Several genes involved in pre-messenger RNA splicing have been shown to be mutated in half of MDS patients, revealing a new leukemic pathway involving spliceosome dysfunction.To characterize the clinical and genetic profile of myeloid neoplasms associated with idic(X)(q13) and i(X)(p10), we performed a retro-spective study, between 2002 and 2017, of 45 patients with myeloid neoplasm who presented these abnormalities.…”