Cytidine deaminase status as a predictive marker in patients with hematologic malignancies treated with azacytidine or cytarabine.

Abstract

7117 Background: Cytarabine 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 is highly polymorphic and dysregulations have been repeatedly associated with poor clinical outcome with gemcitabine. Methods: We have used a test to determine, on a phenotype basis, CDA status in patients. This test was used prospectively in a subset of 39 adult patients (16F, 23M, mean age 77 years), all treated for various haematological malignancies (i.e., CML, AML, lymphomas, 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. Results: In 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%) showed low CDA activities and were considered as PM. Conversely, 8 patients (i.e., 20%) displayed CDA activities particurlary elevated (i.e., > 6U/mg) and were considered as UM patients. Of note, PM patients all showed severe toxicities, including two toxic-deaths. Conversely, UM patients showed little efficacy when treated with either azacytidine or cytarabine. In mice with CDA-deficiency, standard 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. Conclusions: Overall this pilot study strongly 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.