Department of Internal Medicine III, University of Ulm, Ulm, Germany; Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milano, Italy;
Department of Internal Medicine III, University of Ulm, Ulm, Germany;
Blood. 2014 Jun 26;123(26):4027-36. doi: 10.1182/blood-2013-12-546283. Epub 2014 May 5.
The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.
对于 60 岁以上的急性髓系白血病患者，由于疾病特征和患者相关因素不利，其治疗结果仍然较差。基于丙戊酸（VPA）和全反式维甲酸与化疗的体外协同作用，德国-奥地利 AML 研究组 06-04 方案设计。2004 年至 2006 年期间，186 名患者随机分配接受阿糖胞苷、柔红霉素和全反式维甲酸的 2 个诱导周期，要么联合 VPA，要么不联合（标准）。所有患者均给予巩固治疗。由于早期死亡率较高（26%比 14%；P =.06），VPA 组诱导后完全缓解率低于标准组（40%比 52%；P =.14）。VPA 主要毒性为血液学恢复延迟和 3/4 级感染，主要发生在第 2 个诱导周期。在将 VPA 限制在第 1 个诱导周期并降低柔红霉素剂量后，这些毒性降至标准组观察到的水平。中位随访时间为 84 个月后，两组无事件生存和总生存无差异（P =.95 和 P =.57）。然而，VPA 组无复发生存率显著优于标准组（5 年时分别为 24.4%和 6.4%；P =.02）。探索性亚组分析显示，NPM1 突变的急性髓系白血病可能特别受益于 VPA。该试验在 www.clinicaltrials.gov 上注册，编号为#NCT00151255。
