文章：

帕比司他与阿扎胞苷联合表观遗传学靶向治疗急性髓系白血病和高危骨髓增生异常综合征

Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome

原文发布日期：2014-01-10

DOI: 10.1038/bcj.2013.68

类型: Original Article

开放获取: 是

英文摘要：

Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m2 subcutaneously (days 1–5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.

摘要翻译： 

针对老年急性髓系白血病（AML）患者的治疗选择有限。本研究开展了一项Ib/II期临床试验，旨在评估泛组蛋白去乙酰化酶抑制剂帕比司他（LBH589）联合阿扎胞苷在不适合强化化疗的AML或高危骨髓增生异常综合征（MDS）患者中的最大耐受剂量（MTD）及初步疗效。39例患者（AML=29例，MDS=10例）接受阿扎胞苷（75mg/m²皮下注射，第1-5天）和口服帕比司他（自第5天开始，每周三次共七次给药）的28天周期治疗，直至出现毒性反应或疾病进展。在Ib期阶段观察到剂量限制性毒性：0/4例患者（10mg帕比司他组）、1/7例患者（20mg组，表现为疲劳）、1/6例患者（30mg组，表现为疲劳）以及4/5例患者（40mg组，表现为疲劳、晕厥、低钠血症和嗜睡）。在II期阶段，额外17例患者接受MTD剂量30mg的帕比司他治疗。AML患者的总缓解率（ORR=完全缓解+血细胞计数未完全恢复的完全缓解+部分缓解）为31%（9/29），MDS患者为50%（5/10）。中位随访13个月后，AML与MDS患者的中位总生存期分别为8个月和16个月。组蛋白H3和H4乙酰化水平升高是临床响应的有效早期生物标志物。帕比司他联合阿扎胞苷在高危MDS/AML患者中耐受性良好且具有临床活性，值得进一步研究。

原文链接：

Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome