CDA status predicts life-threatening toxicities in AML patients treated with cytarabine

Induction phase with Cytarabine (Ara-C) is a mainstay to treat  accute myeloid leukemia (AML) and severe/lethal toxicities are frequent.  Ara-C is metabolized in the liver by an exclusive enzymatic step by cytidine... [ view full abstract ]

Induction phase with Cytarabine (Ara-C) is a mainstay to treat  accute myeloid leukemia (AML) and severe/lethal toxicities are frequent.  Ara-C is metabolized in the liver by an exclusive enzymatic step by cytidine deaminase (CDA). CDA is a ubiquitous enzyme coded by a highly polymorphic gene, with subsequent phenotypes ranging from poor metabolizer (PM) to ultra metabolizer (UM) patients. To what extent CDA phenotype could help predict clinical outcome in Ara-C-treated patients remains to be established. In this clinical observational study we studied whether CDA deficiency  could be at the origin of severe/lethal toxicities in AML patients undergoing induction phase with Ara-C.  CDA activity and 79A>C CDA genetic polymorphism was evaluated  in 58 adult patients (25F, 33M, mean age 63 ±15 years). All patients were treated following current standard care by Ara-C-containing regimen (i.e., 7+3 protocol) and monitored for toxicity  and response.  Mean CDA activity was 3.14 ± 3 U/mg. The incidence of CDA deficiency was much higher in AML patients (41%) than what we previously observed in patients with solid tumors (i.e., 5-7%). No relationship was found between CDA phenotype and genotype. A total of 20 patients (43%) displayed severe toxicities upon administration, including 3 toxic-deaths (5%). ROC analysis identified a cut-off value in CDA ≤ 2 U/mg associated with increased risk of 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 in 4 patients (7%) whereas 16 patients (27%) had Progressive Disease. No relationship was evidenced between CDA status and response, however PM patients tended to have longer PFS (278 vs. 517 days) and OS (570 days vs. not reached) than EM patients. Overall this proof-of-concept study suggests that CDA could be a relevant marker for predicting clinical outcome in patients treated with Ara-C. This marker could be used next as a covariate to customize Ara-C dosing in AML patients so as to reduce the risk of severe or lethal toxicities.