Outcome and toxicities associated to chemotherapy in children with acute lymphoblastic leukemia and Gilbert syndrome. Usefulness of UGT1A1 mutational screening

Berrueco, Rubén; Alonso‐Saladrigues, Anna; Martorell, Loreto; Català-Temprano, A.; Ruiz-Llobet, Anna; Toll, Teresa; Torrebadell, Montserrat; Naudó, Montserrat; Camós, Mireia; Rives, Susana

doi:10.1002/pbc.25457

Cited by 10 publications

(13 citation statements)

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“…Therefore, therapy should not be cancelled or suspended, and an appropriate therapy schedule can be maintained. Recently, Berrueco et al (27) revealed that pediatric acute lymphoblastic leukemia (ALL) patients homozygous for the UGT1A1*28 allele tended to develop transient hyperbilirubinemia during cancer chemotherapy. They concluded that Gilbert syndrome should be taken into account when bilirubin levels increase without signs of hepatitis or hemolysis.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…The impact of GS on the course of cancers [3] and hematological malignancies in particular remains uncertain. The higher incidence of GS has been reported in childhood acute leukemia (14–20%) [5] , [6] , 7 , but no differences in outcome were found in patients with GS [7] . GS has also been associated with excessive toxicity of anticancer drugs in childhood acute lymphoblastic leukemia [8] , but improved outcomes in adult patients with Hodgkin lymphoma [9] .…”

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confidence: 72%

Can Gilbert's syndrome mitigate chronic lymphocytic leukemia?

Yavorkovsky

Shvidel

2022

Leukemia Research Reports

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“…In a retrospective 159‐patient study, 23 pediatric patients with ALL had a homozygous TA 7 genotype and were treated with regimens containing methotrexate . Maximum bilirubin levels were significantly higher at baseline, 12.1 µmol/L ± 6.3 versus 6.8 µmol/L ± 3.3, p<0.0001 (0.7 mg/dL ± 0.36 vs 0.4 mg/dL ± 0.2), and with each treatment phase of induction, consolidation, intensification, and continuation in the patients with GS (Table ).…”

Section: Agents That May Inhibit Glucuronidationmentioning

confidence: 99%

Oncology Drug Dosing in Gilbert Syndrome Associated with UGT1A1: A Summary of the Literature

Ha¹,

Jupp

Tsang

2017

Pharmacotherapy

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Gilbert syndrome (GS) is a hereditary condition that affects ~10% of the population. It is characterized by intermittent, unconjugated hyperbilirubinemia in the absence of hepatocellular damage and hemolysis. Although GS is often described as a benign laboratory finding, it may alter drug metabolism by decreasing the ability to conjugate drugs. Genetic polymorphisms, specifically the UGT1A1*28 allele, may reduce glucuronidation by 30% that severely impacts the ability to metabolize certain medications. Antineoplastic agents used in oncologic settings have toxic side effects, and alterations in metabolism may result in severe or even life-threatening toxicities. Many of the drug monographs provided by manufacturers contain dose adjustment parameters for hepatic function, using serum bilirubin as a surrogate marker. However, in patients with GS, hepatic function remains normal in the setting of hyperbilirubinemia, and scant literature is available to provide guidance on empirical dosage adjustment. In this review, we conducted a literature search of routinely used oncology medications and assessed the need for empirical dose adjustments in the setting of GS.

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Outcome and toxicities associated to chemotherapy in children with acute lymphoblastic leukemia and Gilbert syndrome. Usefulness of UGT1A1 mutational screening

Abstract: Differences in outcome were not found in patients with GS. Universal screening for GS appears to be not necessary in pediatric patients with ALL. However, when hyperbilirubinemia is observed, it must be rule out in order to avoid unnecessary changes in treatment.

Cited by 10 publications

References 20 publications

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

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

Can Gilbert's syndrome mitigate chronic lymphocytic leukemia?

Oncology Drug Dosing in Gilbert Syndrome Associated with UGT1A1: A Summary of the Literature

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