Abstract: Myelofibrosis (MF) is a clonal hematologic malignancy characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms with a propensity towards leukemic transformation. Constitutive activation of the JAK/STAT pathway is a well-described pathogenic feature of MF. Allogeneic stem cell transplant is the only curative therapy, but due to high morbidity and mortality this option is not available for most patients. There are two approved targeted therapy options for MF, ruxolitinib and fedratinib. In this review, we discuss the clinical utility of fedratinib in the myelofibrosis treatment paradigm. Fedratinib has shown impressive pre-clinical and clinical efficacy in patients with untreated MF as well as in those with ruxolitinib intolerance and those with relapsed/refractory MF. Here, we review the pre-clinical and clinical trials that led to the approval of fedratinib, and the ongoing late-phase trials. We highlight several areas regarding the clinical utility of fedratinib that remain unanswered. We discuss the limitations of fedratinib and address areas that are understudied and require further clinical evaluation and research. The approval of fedratinib has provided a significant expansion to the very limited treatment armamentarium available to patients with MF.

Keywords: myelofibrosis, fedratinib, targeted therapy, JAK inhibitor


中文翻译：

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Fedratinib 在骨髓纤维化中的临床应用


摘要：骨髓纤维化（MF）是一种克隆性血液恶性肿瘤，以骨髓纤维化、髓外造血、脾肿大和全身症状为特征，并有向白血病转化的倾向。 JAK/STAT 通路的组成性激活是 MF 的一个明确的致病特征。同种异体干细胞移植是唯一的治疗方法，但由于高发病率和死亡率，这种选择不适用于大多数患者。 MF 有两种已获批准的靶向治疗方案：ruxolitinib 和 fedratinib。在这篇综述中，我们讨论了 fedratinib 在骨髓纤维化治疗范例中的临床应用。 Fedratinib 在未经治疗的 MF 患者、鲁索替尼不耐受患者和复发/难治性 MF 患者中显示出令人印象深刻的临床前和临床疗效。在这里，我们回顾了促使 fedratinib 获得批准的临床前和临床试验，以及正在进行的后期试验。我们强调了有关 fedratinib 临床效用的几个尚未得到解答的领域。我们讨论了 fedratinib 的局限性，并讨论了尚未充分研究且需要进一步临床评估和研究的领域。 fedratinib 的批准极大地扩展了 MF 患者可用的非常有限的治疗方案。


关键词:骨髓纤维化, fedratinib, 靶向治疗, JAK抑制剂