Pharmacology & Toxicology, Experimental Station, Incyte Corp., Wilmington, DE 19348, USA.
Expert Opin Pharmacother. 2012 Nov;13(16):2397-407. doi: 10.1517/14656566.2012.732998. Epub 2012 Oct 10.
Myelofibrosis (MF) is a debilitating hematologic malignancy characterized by progressive splenomegaly, burdensome symptoms, cytopenias and shortened survival. Chronic alterations in Janus-associated kinase-signal transducer and activator of transcription (JAK-STAT) signaling have been identified in the pathogenesis of MF, making this pathway a target for drug development. Ruxolitinib is the first JAK1 and JAK2 inhibitor to be approved by the US Food and Drug Administration.
This review describes the characteristics of MF, the current therapeutic options and need for effective therapies, the contribution of aberrant JAK-STAT signaling to various disease-specific manifestations and the pharmacodynamics, pharmacokinetics, efficacy and tolerability of ruxolitinib. Articles describing MF disease burden and results of ruxolitinib pre-clinical and clinical trials were identified and summarized.
Conventional MF treatments alleviate some MF symptoms but have limited efficacy, do not modify the natural history of the disease and are not approved for MF. The JAK1 and JAK2 inhibitor ruxolitinib has shown promising results in pre-clinical and clinical trials. In Phase III trials, ruxolitinib was shown to reduce splenomegaly and improve MF-related symptoms. Recent evidence also suggests that ruxolitinib may improve survival. The most common adverse events were anemia and thrombocytopenia, which were managed with dose adjustments (or red blood cell transfusions for anemia).
骨髓纤维化（MF）是一种使人虚弱的血液系统恶性肿瘤，其特征为进行性脾肿大、负担沉重的症状、细胞减少和生存期缩短。在 MF 的发病机制中已经确定了 Janus 相关激酶-信号转导子和转录激活子（JAK-STAT）信号的慢性改变，使得该途径成为药物开发的靶点。芦可替尼是美国食品和药物管理局批准的第一种 JAK1 和 JAK2 抑制剂。
这篇综述描述了 MF 的特征、当前的治疗选择和对有效治疗的需求、异常 JAK-STAT 信号对各种疾病特异性表现的贡献以及芦可替尼的药效学、药代动力学、疗效和耐受性。描述了 MF 疾病负担和芦可替尼临床前和临床试验结果的文章被确定并进行了总结。
常规 MF 治疗可缓解一些 MF 症状，但疗效有限，不能改变疾病的自然史，也未被批准用于 MF。JAK1 和 JAK2 抑制剂芦可替尼在临床前和临床试验中显示出有希望的结果。在 III 期试验中，芦可替尼显示可减少脾肿大和改善 MF 相关症状。最近的证据还表明，芦可替尼可能改善生存。最常见的不良反应是贫血和血小板减少症，可通过调整剂量（或输血治疗贫血）来管理。
