文章：

plitidepsin 治疗原发性骨髓纤维化及真性红细胞增多症/原发性血小板增多症后骨髓纤维化患者的评价：临床前研究及 II 期临床试验结果

Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial

原文发布日期：2015-03-13

DOI: 10.1038/bcj.2015.5

类型: Original Article

开放获取: 是

英文摘要：

Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5 mg/m2 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2–41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5 mg/m2 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted.

摘要翻译： 

先前数据已证实，plitidepsin（一种环状缩肽）在骨髓纤维化（MF）小鼠模型中表现出活性。本文报道的新临床前实验发现，低纳摩尔浓度的plitidepsin能有效抑制JAK2V617F突变细胞系的增殖，并减少MF患者CD34+细胞的集落形成，这至少部分是通过调节p27水平实现的。MF患者的细胞p27含量显著降低，而在plitidepsin作用后略有增加。基于上述前提，一项探索性II期试验评估了plitidepsin 5 mg/m² 3小时静脉输注方案（每4周第1天和第15天给药）。根据国际骨髓纤维化研究与治疗工作组共识标准，在试验第一阶段11名可评估患者中，缓解率为9.1%（95% CI, 0.2–41.3%）。唯一应答者实现了红细胞输注独立，另有9名患者（81.8%）报告疾病稳定。8例患者脾肿大得到短期改善。总之，plitidepsin 5 mg/m² 每4周3小时输注方案耐受性良好，但在原发性、真性红细胞增多症后或原发性血小板增多症后骨髓纤维化患者中疗效有限。因此，该试验提前终止，我们认为plitidepsin作为单药治疗骨髓纤维化的进一步临床试验尚无必要。

原文链接：

Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial