Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis
Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis
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DOI：
10.1182/blood-2009-10-246363
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发表时间：
2010-02-11
期刊：
影响因子：
20.3
通讯作者：
Verstovsek, Srdan
中科院分区：
文献类型：
--
作者：
Santos, Fabio P. S.;Kantarjian, Hagop M.;Verstovsek, Srdan
骨髓纤维化(MF)患者的治疗选择很少，他们的生存时间显著缩短。在大约50%的MF患者中发现JAK2酪氨酸激酶(JAK2V617F)的激活突变。CEP-701是一种酪氨酸激酶抑制剂，在体外和体内实验中都能抑制JAK2。我们对22名JAK2(V617F)阳性的MF患者(每天两次口服80毫克)进行了CEP-701的2期临床研究，其中6名(27%)患者根据国际工作组的标准(所有病例的临床改善)进行了反应：仅脾大小缩小(n=3)，不再输血(n=2)，脾缩小伴细胞减少(n=1)。中位有效时间为3个月，有效时间大于或等于14个月。在骨髓纤维化或JAK2(V617F)等位基因负荷方面未见改善。在治疗期间，应答者的磷酸化STAT3水平比基线有所下降。8名患者(36%)经历了3级或4级毒性，6名患者(27%)需要减少剂量。主要不良反应为骨髓抑制(3级或4级贫血，14%；血小板减少，23%)和胃肠道反应(腹泻，任一级，72%；3级或4级，9%；恶心，仅1级或2级，50%；呕吐，1级或2级，27%)。总之，CEP-701对MF患者的疗效不高，胃肠道毒性轻微但频繁。这项研究在http://clinicaltrials.gov注册为NCT00494585。(血。2010；115：1131-1136)
Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2V617F) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2(V617F)-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2(V617F) allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression ( grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances ( diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585. (Blood. 2010;115:1131-1136)