Cytidine Deaminase Status As a Predictive Marker Of Response and Toxicity In Patients With Haematological Malignancies Treated With Azacytidine Or Cytarabine

Abstract

BackgroundCytarabine and azacytidine are mainstays for treating haematological malignancies. As most nucleosidic analogs, both azacytidine and cytarabine are metabolized in the liver by an exclusive enzymatic step driven by cytidine deaminase (CDA). CDA expression polymorphism has been associated with clinical outcome in patients treated with gemcitabine. MethodsWe determined CDA levels in 39 adult patients (16F, 23M, mean age 77 years), treated mainly for AML and myelodysplastic syndromes with either aza-cytidine or a cytarabine-containing regimen. Response and treatment-related toxicities were monitored following current standards. In addition, impact of CDA status on azacytidine tolerance was evaluated in mice with or without CDA deficiency, as a proof of concept for the actual implication of metabolic deregulations in the toxicities observed in patients. ResultsIn patients, mean CDA activity was 3.7 +/-2.8 U/mg (min: 1, max: 14.8 U/mg). Ten out of 39 patients (i.e., 25%) had low CDA activities and were considered as poor metabolizers (PM). Conversely, 8 patients (i.e., 20%) displayed high CDA activities (i.e., > 6U/mg) and were considered as high metabolizers (HM). PM showed severe toxicities, including two toxic-deaths. Conversely, HM showed little efficacy when treated with either azacytidine or cytarabine. In mice with CDA-deficiency, standard dose azacytidine led to profound and long-lasting neutropenia, as compared with normal mice. Drug monitoring confirmed that individuals with low CDA activity and toxicities showed higher concentrations of azacytidine as compared with normal individuals. Conclusionsthis study suggests that CDA status could be a relevant marker for predicting clinical outcome in patients treated with either azacytidine or cytarabine. CDA status could be further used as a covariate to tailor drug dosage so as to ensure an optimal efficacy/toxicity balance in patients with haematological malignancies. Disclosures:No relevant conflicts of interest to declare.