SMARTc Unit, Pharmacokinetics Laboratory, Unité Mixte de Recherche (UMR) INSERM U1068 Centre de Recherche en Cancerologie de Marseille, Aix Marseille University, Marseille, France.
Hematology and Cellular Therapy Department, La Conception University Hospital of Marseille, Marseille, France.
Blood Adv. 2018 Mar 13;2(5):462-469. doi: 10.1182/bloodadvances.2017014126.
Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the allelic variant) were performed in 58 adult patients with AML treated with the standard 7+3 (Ara-C + anthracyclines) protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 ± 0.7 U/mg vs 3.95 ± 3.1 U/mg; Student test < .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 ± 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C.
阿糖胞苷（Ara-C）是急性髓系白血病（AML）化疗的基础。关于可能的预测因素，人们知之甚少，这些因素可能与 Ara-C 引起的频繁（即高达 16%）危及生命或致命的毒性有关。Ara-C 在肝脏中被一种称为胞苷脱氨酶（CDA）的单一酶解毒，该基因编码的产物已知高度多态性。在这项概念验证研究中，我们特别研究了 CDA 弱代谢者（PM）表型在 Ara-C 毒性中的作用。在 58 例接受标准 7+3（Ara-C +蒽环类药物）方案治疗的 AML 成年患者中进行了 CDA 表型（血清中 CDA 残留活性的测量）和基因分型（寻找等位基因变异）。与未发生严重/致命毒性的患者相比，发生严重/致命毒性的患者的 CDA 活性明显降低（1.5±0.7 U/mg 比 3.95±3.1 U/mg；Student 检验<.001）。随后的受试者工作特征分析确定了与 PM 综合征相关的 CDA 活性阈值（即 2 U/mg），并增加了发生严重毒性的风险。5%的患者发生了致命毒性，所有患者均显示 CDA PM 状态（1.3±0.5 U/mg）。在疗效方面，低 CDA 活性的患者观察到更高的反应率、更长的无进展生存期和总生存期。综上所述，这项研究的结果强烈表明，CDA 是接受标准 Ara-C 诱导治疗的 AML 患者发生危及生命的毒性的预测标志物。
