Department of Leukemia, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77025, USA.
J Clin Oncol. 2012 Jun 20;30(18):2204-10. doi: 10.1200/JCO.2011.38.3265. Epub 2012 May 14.
To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).
Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely.
After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival.
The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.
评估组蛋白去乙酰化酶抑制剂伏立诺他联合伊达比星和阿糖胞苷（阿糖胞苷）治疗初治急性髓系白血病（AML）或骨髓增生异常综合征（MDS）患者的安全性和疗效。
患者为年龄在 15 至 65 岁之间、有适当器官功能且无核心结合因子异常的初治 AML 或高危 MDS。诱导治疗方案为伏立诺他 500mg，每日口服 3 次（第 1-3 天），伊达比星 12mg/m2静脉滴注（IV），每日 1 次（第 4-6 天），阿糖胞苷 1.5g/m2，IV 持续输注，每日 1 次，连用 4 天（第 4-7 天）。缓解的患者可接受 5 个周期的巩固治疗和长达 12 个月的单药伏立诺他维持治疗。如果毒性过大或中位无事件生存（EFS）超过 28 周的可能性较低，则计划提前终止研究。
在三例患者入组阶段后，共治疗了 75 例患者。中位年龄为 52 岁（范围为 19-65 岁），29 例（39%）患者核型正常，11 例（15%）患者存在 FLT-3 内部串联重复（ITD）。未观察到与伏立诺他相关的毒性增加。诱导死亡率为 4%。EFS 为 47 周（范围为 3-134 周），总生存（OS）为 82 周（范围为 3-134 周）。总缓解率（ORR）为 85%，包括 76%完全缓解（CR）和 9%CR 伴不完全血小板恢复。二倍体患者的 ORR 为 93%，FLT-3 ITD 患者的 ORR 为 100%。NRF2 和 CYBB 的水平与生存时间延长相关。
伏立诺他联合伊达比星和阿糖胞苷在 AML 中安全有效。
