Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX, 77030, USA.
Curr Treat Options Oncol. 2019 Jan 24;20(1):5. doi: 10.1007/s11864-019-0604-y.
Seven years after the approval of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib, it remains the only drug licensed for the treatment of myelofibrosis. Patients who discontinue ruxolitinib have a dismal outcome, and this is, therefore, an area of significant unmet need. Given the central role that JAK-signal transducer and activator of transcription (STAT) activation plays in disease pathogenesis, there have been many other JAK inhibitors tested, but most have been abandoned, for a variety of reasons. The JAK2-selective inhibitor fedratinib has recently been resurrected, and there has been a resurgence of interest in the failed JAK1/2 inhibitor momelotinib, which possibly improves anemia. Pacritinib, a non-myelosuppressive JAK2-selective inhibitor, is currently in a dose-ranging study mandated by regulatory authorities. A plethora of other targeted agents, most backed by preclinical data, are in various stages of investigation. These include epigenetic and immune therapies, agents targeting cellular survival, metabolic and apoptotic pathways, the cell cycle, DNA repair, and protein folding and degradation, among others. However, at this time, none of these is close to registration or even in a pivotal trial, illustrating the difficulties in recapitulating the clinical disease in preclinical models. Most current clinical trials are testing the addition of a novel agent to ruxolitinib, either in the frontline setting or in the context of an insufficient response to ruxolitinib, or attempting to study new drugs in the second-line, "ruxolitinib failure" setting. Emerging data supports the addition of azacitidine to ruxolitinib in some patients. Other strategies have focused on improving cytopenias, through amelioration of bone marrow fibrosis or other mechanisms. This is important, because cytopenias are the commonest reason for ruxolitinib interruption and/or dose reduction, and dose optimization of ruxolitinib is tied to its survival benefit. The activin receptor ligand trap, sotatercept, and the anti-fibrotic agent, PRM-151, have shown promise in this regard.
罗昔替尼获批用于治疗骨髓纤维化 7 年后，它仍然是唯一获准用于治疗骨髓纤维化的药物。停止使用罗昔替尼的患者预后不良，因此这是一个存在巨大未满足需求的领域。鉴于 JAK-信号转导子和转录激活子（STAT）激活在疾病发病机制中的核心作用，已经有许多其他 JAK 抑制剂进行了测试，但由于各种原因，大多数都被放弃了。JAK2 选择性抑制剂 fedratinib 最近被重新启用，对失败的 JAK1/2 抑制剂 momelotinib 的兴趣也重新燃起，该药物可能改善贫血。非骨髓抑制性 JAK2 选择性抑制剂 pacritinib 目前正在进行监管机构要求的剂量范围研究。大量其他靶向药物，大多数都有临床前数据支持，处于不同的研究阶段。这些药物包括表观遗传和免疫疗法、靶向细胞存活、代谢和凋亡途径、细胞周期、DNA 修复以及蛋白质折叠和降解的药物等。然而，目前这些药物都没有接近注册，甚至没有进入关键试验，这说明了在临床前模型中重现临床疾病的困难。大多数当前的临床试验都在测试将一种新的药物添加到 ruxolitinib 中，无论是在一线治疗还是在对 ruxolitinib 反应不足的情况下，还是试图在二线治疗中研究新药，即“ruxolitinib 失败”的情况下。新出现的数据支持在某些患者中添加阿扎胞苷到 ruxolitinib 中。其他策略侧重于通过改善骨髓纤维化或其他机制来改善细胞减少症。这很重要，因为细胞减少症是 ruxolitinib 中断和/或剂量减少的最常见原因，而 ruxolitinib 的剂量优化与其生存获益相关。激活素受体配体陷阱 sotatercept 和抗纤维化药物 PRM-151 在这方面显示出了希望。
