Polymorphism of UGT1A1 and Frequency of Hyperbilirubinemia in Patients with Chronic Myeloid Leukemia Treated By Nilotinib

Background. Isolated hyperbilirubinemia mostly of indirect bilirubin fraction is diagnosed in patients with polymorphism of UGT1A1 gene (Gilbert's syndrome), mainly homozygous genotype (TA)₇/(TA)₇ which encodes the enzyme uridinediphosphoglycosyltransferase 1 (UDP-GT) in hepatocytes. Hyperbilirubinemia is also frequent laboratory abnormality in chronic myeloid (CML) patients treated by nilotinib. Connection of hyperbilirubinemia with UGT1A1 polymorphism in CML patients on nilotinib therapy requires understanding and studying.

Aims. To estimate the correlation between polymorphism of UGT1A1 gene and frequency of hyperbilirubinemia in patients with CML treated by nilotinib.

Methods. We estimated biochemical parameters in a group of 100 patients treated by nilotinib: bilirubin, transaminases (AST, ALT), persistence of hyperbilirubinemia and biochemical parameters normalization. We also considered patients’ anamnesis for hepatitis and estimated those laboratory abnormalities in previous imatinib therapy as 98 of 100 patients received nilotinib second line after imatinib.

Me time of observation on nilotinib therapy was 36.7 months (range 1 – 94.5).

Men/women ratio was 45/55. Promoter region of the UGT1A1 gene was studied by allele specific polymerase chain reaction (AS-PCR).

Results. Hyperbilirubinemia due to the indirect bilirubin fraction was observed in 84 (84%) of 100 patients. Of those 84 patients hyperbilirubinemia grade 1 was in 41 (49%), grade 2 in 33 (39%), grade 3 in 10 (12%). Normal genotype (TA)₆/(TA)₆ was in 71 (71%) patients, heterozygous genotype (TA)₆/(TA)₇ in 19 (19%), homozygous genotype (TA)₇/(TA)₇ in 10 (10%) patients. Frequency of hyperbilirubinemia grade 1-3 in patients depending on genotype is presented in table1.

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Hyperbilirubinemia grade 1 was associated mostly with normal genotype patients, grade 2 with normal and abnormal genotype, grade 3 with abnormal and homozygous genotype (9 of 10 patients). In 1 patient with normal genotype grade 3 hyperbilirubinemia was due to intracellular hemolysis approved by laboratory tests. One patient with heterozygous form (TA₆/TA₇) and normal bilirubin was on nilotinib <1 month.

Hyperbilirubinemia on previous imatinib treatment was in 29 (35,7%) of 82 patients with second line nilotinib: grade 1 in 25 (86.2%) of 29 patients (homozygous genotype TA₇/TA₇ in 5 of 25), grade 2 in 4 (13.8%) of 29 patients (all with homozygous genotype TA₇/TA₇). Normal bilirubin levels were in 55(46,3%) of 82 patients on previous imatinib therapy. One patient with TA₇/TA₇ genotype received nilotinib as first line.

Bilirubin levels normalized in 48 (57.2%) of 84 patients during 1 to 3 months and persisted in 36 (42.8%).

In 8(9,5%) of 84 patients transient ALT and AST elevation was observed: grade 1(1), grade 2 (5) grade 3-4(2); it was resolved and only isolated hyperbilirubinemia was observed later on. In 2 of 84 patients hepatitis C was diagnosed.

No treatment discontinuation was done due to hyperbilirubinemia.

Summary/Conclusion. In CML patients on nilotinib treatment Grade 3 hyperbilirubinemia as well as previous history of hyperbilirubinemia any grade on imatinib can be a sign of homozygous genotype TA₇/TA₇. Lower grades of hyperbilirubinemia occur both in patients with normal and abnormal heterozygous genotype. Other reasons for hyperbilirubinemia (hemolysis, hepatitis) should be assessed. No connection of UGT1A1 polymorphism and transaminase (ALT,AST) elevation was established.