Ancestry and pharmacogenetics of antileukemic drug toxicity

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

*Corresponding author for this work

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

Treatment-related toxicity in acute lymphoblastic leukemia (ALL) can not only be life threatening but may also affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex, and disease risk group (lower- vs higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurologic) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR], 6.85 [95% confidence interval [CI], 1.73-27.0]) and cytochrome P4503A5 (OR, 4.61 [95% CI, 1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR, 10.4 [95% CI, 1.35-80.4]) as it also did during continuation (OR, 2.01 [95% CI, 1.06-4.11]). In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (P = .017, P < .001, and P < .001) and methotrexate clearance (P = .028), which was also independently associated with hyperbilirubinemia (P = .026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy.

Original languageEnglish (US)
Pages (from-to)4151-4157
Number of pages7
JournalBlood
Volume109
Issue number10
DOIs
StatePublished - May 15 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Kishi, S., Cheng, C., French, D., Pei, D., Das, S., Cook, E. H., Hijiya, N., Rizzari, C., Rosner, G. L., Frudakis, T., Pui, C. H., Evans, W. E., & Relling, M. V. (2007). Ancestry and pharmacogenetics of antileukemic drug toxicity. Blood, 109(10), 4151-4157. https://doi.org/10.1182/blood-2006-10-054528