Cytarabine (Ara-C) is the backbone for treating accute myeloid leukemia (AML). As most nucleoside analogs, Ara-C is metabolized in the liver by an exclusive enzymatic step driven by cytidine deaminase (CDA). CDA is a ubiquitous enzyme that proved to be highly polymorphic, with activities in patients ranging from poor metabolizer (PM) to ultra metabolizer (UM). To date, deregulated CDA has been evidenced as a culprit for life-threatening toxicities with gemcitabine. Little evidences have been collected thus far about the possible role erratic CDA could further play with Ara-C. Here, we investigated whether deregulations affecting CDA could be at the origin of unexpectedly severe, and sometimes lethal, toxicities with Ara-C in patients with AML. In this clinical observational study we determined CDA activity levels and searched for CDA genetic polymorphisms in 58 adult patients (25F, 33M, mean age 63 ±15 years) hospitalized for AML and scheduled for induction therapy. All patients were treated following current standard care by Ara-C-containing regimen (i.e., 7+3 protocol) and monitored for toxicity (CTCAEv4 grading) and response. Efficacy was evaluated one-month after starting the induction protocol. Mean CDA activity in the studied population was 3.14 ± 3 U/mg. No relationship was found between CDA phenotype and genotype (i.e., 79A>C polymorphism). A total of 20 patients (43%) displayed severe toxicities (i.e. grade-3 and above) upon administration, including 3 unrecoverable grade-5 toxicities (5%). Relationship between CDA activity and severe toxicity was investigated using ROC analysis. We observed that the incidence of CDA deficiency was much higher in AML patients (40%) than what we previously observed in patients with solid tumors. A cut-off value in CDA ≤ 2 U/mg was associated with increased risk of experiencing severe/lethal toxicities with 74% sensitivity and 65% specificity. Among the 20 patients with severe toxicities, 14 (72 %) were categorized as PM. Importantly, patients who experienced lethal toxicities were all profoundly PM patients. CR was achieved in 35 patients (60%), CRI achieved in 4 patients (7%) whereas 16 patients (27%) failed to respond (PD). No relationship was evidenced between CDA status and response, however regardless of the karyotype we observed that PM patients tended to have longer PFS (278 vs. 517 days) and OS (570 days vs. not reached) as compared with EM patients. Overall this proof-of-concept study strongly suggests that CDA status could be a relevant marker for predicting clinical outcome in patients treated with Ara-C, especially treatment-induced toxicities. A prospective study including full PK and pharmacogenetics support is currently ongoing in our institute to confirm these observations. Should the role CDA plays be confirmed, this marker could be used as a covariate to customize Ara-C dosing in AML patients.

Citation Format: Raphaelle Fanciullino, Laure Farnault, Mélanie Donnette, Vadim Ivanov, Geoffroy Venton, Joseph Ciccolini, Yael Berda-Haddad, Catherine Roche, L'Houcine Ouafik, Bruno Lacarelle, Regis Costello. CDA predicts life-threatening toxicities in AML patients treated with cytarabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3898.