A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia
A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia
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DOI：
10.1038/sj.leu.2404816
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发表时间：
2007-09-01
期刊：
影响因子：
11.4
通讯作者：
Tefferi, A.
中科院分区：
文献类型：
--
作者：
Mesa, R. A.;Camoriano, J. K.;Tefferi, A.
原发性骨髓纤维化(PMF)或真性红细胞增多症或原发性血小板增多症后骨髓纤维化(PV/ET MF后)患者的治疗选择有限。法尼基转移酶抑制剂替法尼布在体外抑制这类患者的髓系祖细胞的增殖。在目前的II期临床试验中，34名有症状的PMF患者(28例)或PV/ET后MF患者(6例)接受了单药口服替法尼布(300 mg，每日2次，共28天)。终止方案治疗的中位时间为4.6个月；提前终止的原因(n 19；56%)包括疾病进展(21%)和药物不良反应(18%)。毒副反应(3级)包括骨髓抑制16例，神经病变2例，乏力1例，皮疹1例，低钠血症1例。肝脾肿大有效率为33%，需输血贫血有效率为38%。骨髓纤维化、血管生成或细胞遗传学状态未见明显变化。治疗前和治疗后患者样本的体外髓系集落生长分析显示，后者显著减少。临床反应与菌落生长程度、定量JAK2(V617F)水平的可测量下降或在预处理样本中看到的替法尼IC50值(中位数11.8 NM)均不相关。目前的研究表明，替普法尼在PMF和PV/ET术后MF中具有体外和体内活性。
Patients with primary myelofibrosis ( PMF) or post- polycythemia vera or post- essential thrombocythemia myelofibrosis ( post- PV/ ET MF) have limited therapeutic options. The farnesyltransferaseinhibitor tipifarnib inhibits in vitro proliferation of myeloid progenitors from such patients. In the current phase II clinical trial, single- agent oral tipifarnib ( 300mg twice daily *21 of 28 days) was given to 34 symptomatic patients with either PMF ( n 28) or post- PV/ ET MF ( n 6). Median time to discontinuation of protocol therapy was 4.6 months; reasons for early termination ( n 19; 56%) included disease progression ( 21%) and adverse drug effects ( 18%). Toxicities ( >= grade 3) included myelosuppression ( n 16), neuropathy ( n 2), fatigue ( n 1), rash ( n 1) and hyponatremia ( n 1). Response rate was 33% for hepatosplenomegaly and 38% for transfusion- requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis or cytogenetic status. Pre- and post- treatment patient sample analysis for in vitro myeloid colony growth revealed substantial reduction in the latter. Clinical response did not correlate with either degree of colony growth, measurable decrease in quantitative JAK2 (V617F) levels or tipifarnib IC50 values ( median 11.8 nM) seen in pretreatment samples. The current study indicates both in vitro and in vivo tipifarnib activity in PMF and post- PV/ ET MF.