Ancestry and pharmacogenetics of antileukemic drug toxicity

Kishi, Shinji; Cheng, Cheng; French, Deborah; Pei, Deqing; Das, Soma; Cook, Edwin H.; Hijiya, Nobuko; Rizzari, Carmelo; Rosner, Gary L.; Frudakis, Tony; Pui, Ching Hon; Evans, William E.; Relling, Mary V.

doi:10.1182/blood-2006-10-054528

Cited by 182 publications

(181 citation statements)

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“…According to the Japanese Pediatric Leukemia/ Lymphoma Study Group protocol, cancer chemotherapy should be cancelled or delayed in the hyperbilirubinemic group to avoid lethal AEs. However, delayed chemotherapy increases the risk for relapse and insufficient induction of leukemia (1).…”

Section: Discussionmentioning

confidence: 99%

“…In certain cases, according to the therapy protocol, chemotherapy must be suspended when such hyperbilirubinemia presents. Delayed chemotherapy poses a risk for patients in achieving or maintaining remission of the leukemia (1). We previously reported an association between chemotherapy-induced unconjugated hyperbilirubinemia and mutations of a bilirubin uridine-5-diphosphate (UDP)-glucuronosyltransferase gene: UDP-glucuronosyltransferase family 1, polypeptide A1 (UGT1A1) (2).…”

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confidence: 99%

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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%

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confidence: 99%

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

et al. 2016

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“…2,11,12,14,15,26,27 Most of these studies did not find significant associations between the 677T allele and toxicity, 2,12,14,26,27 although one study reported a lower rate of episodes of toxicity among patients carrying the 677T allele 15 and another study showed that individuals with the 677T allele more frequently had to interrupt methotrexate treatment, suggesting that the MTHFR 677C>T serves as a predictor of toxicity during maintenance chemotherapy. 11 These different results are probably attributable to several factors including the methotrexate-dose, treatment protocol, ethnic background, and number of patients analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…2 Prediction of toxicity is difficult because of wide interpatient variation in pharmacokinetics and pharmacodynamics of antileukemic agents and because the same toxicity can be attributable to different drugs.…”

Section: Introductionmentioning

confidence: 99%

“…MTHFR 677 C>T 9 and 1298 A>C) 10 can influence the effectiveness and the toxic effects of methotrexate. The relationship between polymorphisms affecting folate metabolism and methotrexate-related toxicity has been studied mainly in childhood ALL, 2,[11][12][13][14][15] while only a few studies have investigated this relationship in adult patients with hematologic diseases. 16,17 In particular, in adult ALL only MTHFR polymorphisms have been investigated and associated with increased methotrexaterelated toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

Ongaro¹,

Mattei²,

Porta³

et al. 2009

Haematologica

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BackgroundThe antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and MethodsThe aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. ResultsPolymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13-21.95 and odds ratio 4.57, 95%confidence interval 1.01-20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38-33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00-36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46-8.45). ConclusionsGenotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. Haematologica 2009;94:1391-1398. doi:10.3324/haematol.2009 This is an open-access paper.Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

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Genome-wide Interrogation of Germline Genetic Variation Associated With Treatment Response in Childhood Acute Lymphoblastic Leukemia

Yang

Cheng

Yang

et al. 2009

JAMA

203

167

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EDIATRIC ACUTE LYMPHOBLAStic leukemia (ALL) cure rates have increased from less than 10% in the 1960s to more than 80% today. Such advancement was partly derived from the identification of presenting clinical features (eg, molecular subtype, leukocyte count, age) associated with treatment outcome and subsequent implementation of risk-adapted therapy. 1,2 The assessment of decreasing disease bur-den in response to therapy by sequential monitoring of minimal residual disease (MRD) status has n o w b e e n i n t e g r a t e d i n t o r i s k stratification. [3][4][5] Minimal residual dis-See also Patient Page.

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Ancestry and pharmacogenetics of antileukemic drug toxicity

Cited by 182 publications

References 43 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

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

Genome-wide Interrogation of Germline Genetic Variation Associated With Treatment Response in Childhood Acute Lymphoblastic Leukemia

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