The role of JAK1/2 inhibitors in the treatment of chronic myeloproliferative neoplasms.
The role of JAK1/2 inhibitors in the treatment of chronic myeloproliferative neoplasms.
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DOI：
10.1200/edbook_am.2013.33.301
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Harrison, Claire
中科院分区：
文献类型：
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作者：
Keohane, Clodagh;Mesa, Ruben;Harrison, Claire
2005年，JAK2V617F突变的描述首次为骨髓增生性肿瘤的快速诊断和新型治疗提供了分子关键。2007年，第一种药物INC18424，ruxolitinib，JAKALINE或JAKAVI首次在中危2或高危骨髓纤维化患者中进行测试，无论他们是否具有JAK2V617F突变。用这种药物治疗的患者脾肿大明显减轻，症状也明显减轻，在某些情况下症状消退。这项研究之后是两项口服JAK抑制剂治疗的对照骨髓纤维化研究（COMFORT）试验（首次骨髓纤维化III期试验），证实这些方面的结果上级安慰剂或标准治疗，更新的结果显示这种疗法的生存优势。本文讨论了这些结果和其他JAK抑制剂的数据，同时推测这些疗法的未来。它还反映了这样一个事实，即真正的目标和代理人的行动方式是不确定的。与慢性粒细胞白血病（CML）的靶向治疗不同，这些药物不提供分子缓解，目前尚不清楚它们的主要益处是否通过JAK2，JAK1或两者介导。尽管如此，JAK抑制剂的出现是一个受欢迎的进步，并对这些疾病的治疗前景做出了巨大的改善。
In 2005, the description of the JAK2V617F mutation for the first time provided a molecular key to enable more rapid diagnosis and target for novel therapeutics in the myeloproliferative neoplasms. In 2007, the first-in-class agent INC18424, ruxolitinib, JAKafi, or JAKAVI was first tested in patients with intermediate-risk 2 or high-risk myelofibrosis regardless of whether they possessed the JAK2V617F mutation. Patients treated with this agent had major reduction in splenomegaly as well as impressive reduction, and in some cases resolution, of symptoms. This study was followed by the two Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy (COMFORT) trials (the first-ever phase III trials in myelofibrosis), which confirmed results in these aspects were superior to either placebo or standard care, and updated results show a survival advantage with this therapy. This paper discusses these results and data from other JAK inhibitors while speculating on the future of these therapies. It also reflects on the fact that the true targets and agents' mode of action are uncertain. Unlike targeted therapy for chronic myeloid leukemia (CML), these agents do not deliver molecular remission, and it is not clear whether their predominant benefit is mediated via JAK2, JAK1, or both. Nonetheless, the advent of the JAK inhibitor is a welcome advance and has made a dramatic improvement to the therapeutic landscape of these conditions.