title: Lethal toxicity after administration of azacytidine: implication of the cytidine deaminase-deficiency syndrome.
abstract: Azacytidine, an antimetabolite with an original epigenetic mechanism of action, increases survival in patients diagnosed with high-risk myelodysplasic syndromes or acute myeloid leukemia with less than 30% medullar blasts. Azacytidine is a pyrimidine derivative that undergoes metabolic detoxification driven by cytidine deaminase (CDA), a liver enzyme whose gene is prone to genetic polymorphism, leading to erratic activity among patients. Clinical reports have shown that patients with the poor metabolizer (PM) phenotype are likely to experience early severe or lethal toxicities when treated with nucleosidic analogs such as gemcitabine or cytarabine. No clinical data have been available thus far on the relationships between CDA PM status and toxicities in azacytidine-treated patients. Here, we measured CDA activity in a case of severe toxicities with fatal outcome in a patient undergoing standard azacytidine treatment. Results showed that the patient was PM (i.e. residual activity reduced by 63%), thus suggesting that an impaired detoxification step could have given rise to the lethal toxicities observed. This case report calls for further prospective studies investigating the exact role that CDA status plays in the clinical outcome of patients treated with azacytidine.
authors: aSMARTc Unit, Pharmacokinetics Laboratory, UMR_911 CRO2 AMU bPharmacy Unit cOnco-Hematology Unit dHematology Laboratory, La Conception University Hospital of Marseille eTransfer Oncology Laboratory, Nord University Hospital of Marseille, APHM, Marseille, France.
authors: Raphaelle
authors: R
authors: Fanciullino
authors: Cedric
authors: C
authors: Mercier
authors: Cindy
authors: C
authors: Serdjebi
authors: Yaël
authors: Y
authors: Berda
authors: Frederic
authors: F
authors: Fina
authors: L'Houcine
authors: L
authors: Ouafik
authors: Bruno
authors: B
authors: Lacarelle
authors: Joseph
authors: J
authors: Ciccolini
authors: Regis
authors: R
authors: Costello
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D001374:Azacitidine / Q000009:adverse effects*; D003561:Cytarabine / Q000009:adverse effects / Q000633:toxicity; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000235:genetics; D017809:Fatal Outcome; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D001374:Azacitidine; D000093542:Gemcitabine