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

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.

• Authors: 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
• Journal: British journal of haematology (Br J Haematol) Vol. 144 Issue 3 Pg. 388-94 (Feb 2009) ISSN: 1365-2141 [Electronic] England
• PMID: 19036079 (Publication Type: Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Cytarabine
• Cytosine Deaminase

Topics

• Adolescent
• Adult
• Antimetabolites, Antineoplastic (adverse effects, therapeutic use)
• Case-Control Studies
• Child
• Child, Preschool
• Cytarabine (adverse effects, therapeutic use)
• Cytosine Deaminase (genetics)
• Ethnicity
• Genotype
• Humans
• Infant
• Kaplan-Meier Estimate
• Leukemia, Myeloid, Acute (drug therapy, genetics, mortality)
• Randomized Controlled Trials as Topic
• Survival Rate
• Young Adult