Abstract 2208: Cytidine deaminase deficiency and severe toxicities upon aza-cytidine intake: Clinical observations and experimental evidences.
Authors: Raphaelle Fanciullino, Cindy Serdjebi, Severine Mollard, Regis Costello, L'Houcine Ouafik, Joseph Ciccolini, Cedric Mercier
Journal: Cancer Research (2013)

Abstract Azacytidine is a nucleosidic analog used for treating a variety of haematological malignancies. Azacytidine pharmacokinetics is dependent upon a liver detoxification step driven by cytidine deaminase (CDA). CDA is affected by several genetic polymorphisms leading to a wide inter-individual variability in resulting enzymatic activities. In particurlar, dysregulated CDA has been associated with life-threatening toxicities with several nucleosidic analogs such as after cytarabine, capecitabine and gemcitabine intake. However, little is known about the impact of CDA deficiency on the clinical outcome of patients treated with azacytidine. In our institute, a lethal toxicity after pancytopenia has been observed with a 82-years old female patient upon aza-cytidine intake. CDA deficiency was evidenced after retrospective phenotyping (functional activity was found to be reduced by 65% as compared with standard CDA values: 1.2 VS. 3.5 U/mg), thus strongly suggesting that impaired ability to detoxify azacytidine could be the culprit indeed for this case. To further establish the exact role CDA-deficiency could have played in this toxic-death, a non-clinical study was undertaken in rodents. To mimic CDA deficiency, 8 mice were pre-treated with 100 mg/kg of tetrahydrouridine I.P. before being administered with 24 mg/kg of azacytidine. Another group of 8 mice received 24 mg/kg azacytidine only, and were therefore considered as control-CDA. Four mice were used as untreated controls when evaluating tolerance to the treatment. Neutrophils were monitored by flow-cytometry before and after treatment over 10 days as a surrogate marker for global azacytidine-related toxicities. CDA was measured using the same test than the one used at bedside and showed that the two groups differed markedly in their CDA phenotypes (ie, 7.7 VS. 0.98 U/mg) and that deep CDA deficiency (Poor Metabolizer: PM status) was achieved indeed in THU-treated animals. Pharmacokinetics study was carried out on a satellite group (T10, T20, T40 and T60 min) by revered-phase HPLC-UV analysis and showed a marked overexposure in azacytidine plasma levels in PM animals displaying CDA-deficiency. In full line with this observation, longer and deeper neutropenia was observed in this PM subset, as compared with the mice with normal CDA activity treated with the same dosage of azacytidine. Overall, our experimental data strongly support the hypothesis that CDA deficiency is a condition associated with increased risk to undergo life-threatening toxicities after azacytidine treatment. Detecting PM patients should help to secure the use of azacytidine at bedside. Citation Format: Raphaelle Fanciullino, Cindy Serdjebi, Severine Mollard, Regis Costello, L'Houcine Ouafik, Joseph Ciccolini, Cedric Mercier. Cytidine deaminase deficiency and severe toxicities upon aza-cytidine intake: Clinical observations and experimental evidences. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2208. doi:10.1158/1538-7445.AM2013-2208