Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia

Deepika Bhatla, Robert B. Gerbing, Todd A. Alonzo, Heather Conner, Julie A. Ross, Soheil Meshinchi, Xiaowen Zhai, Tiffany Zamzow, Parinda A. Mehta, Hartmut Geiger, John Perentesis, Stella M. Davies

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Cytosine arabinoside (ara-C) is irreversibly deaminated to a non-toxic metabolite by cytidine deaminase (CDA). A common polymorphism, A79C, in the gene encoding cytidine deaminase (CDA) changes a lysine residue to glutamine resulting in decreased enzyme activity. CDA A79C genotypes were determined in 457 children with acute myeloid leukaemia (AML) treated on the Children's Cancer Group (CCG) 2941 and 2961 protocols and analyzed the impact of CDA genotype on therapy outcomes. Postinduction treatment-related mortality (TRM) was significantly elevated in children with the CC genotype (5-year TRM 17 ± 13% CC vs. 7 ± 4% AA, 5 ± 4% AC, P = 0.05). This was more notable in children who received idarubicin, fludarabine, ara-C, and granulocyte colony-stimulating factor (IDA-FLAG; ara-C = 7590 mg/m2) (5-year TRM 24 ± 21% CC vs. 6 ± 6% AA, 6 ± 7% AC, P = 0.07) as consolidation therapy compared to idarubicin, dexamethasone, cytarabine, thioguanine, etoposide and daunomycin (IDA-DCTER; ara-C = 800 mg/m2) (5-year TRM 15 ± 20% CC vs. 8 ± 6% AA, 4 ± 6% AC; P = 0.29). Relapse-free survival was non-significantly increased in children with the CC genotype treated with IDA-FLAG (76 ± 20% CC vs. 59 ± 12% AA and 55 ± 14% AC; P = 0.40). These data indicate that children with a low activity CDA genotype are at increased risk of TRM with ara-C based therapy for AML.

Original languageEnglish (US)
Pages (from-to)388-394
Number of pages7
JournalBritish journal of haematology
Volume144
Issue number3
DOIs
StatePublished - Feb 2009

Keywords

  • Acute myeloid leukaemia
  • Cytidine deaminase genotype
  • Cytosine arabinoside therapy
  • Toxicity

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