Waksal Julian A, Tremblay Douglas, Mascarenhas John
Department of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Onco Targets Ther. 2021 Aug 21;14:4509-4521. doi: 10.2147/OTT.S267001. eCollection 2021.
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.
骨髓纤维化（MF）是一种克隆性血液系统恶性肿瘤，其特征为骨髓纤维化、髓外造血、脾肿大以及全身症状，并倾向于发生白血病转化。JAK/STAT通路的组成性激活是MF一种广为人知的致病特征。异基因干细胞移植是唯一的治愈性疗法，但由于高发病率和死亡率，大多数患者无法采用此方案。目前有两种已获批用于MF的靶向治疗药物，即芦可替尼和非格司亭。在本综述中，我们讨论非格司亭在骨髓纤维化治疗模式中的临床应用。非格司亭在未经治疗的MF患者、芦可替尼不耐受患者以及复发/难治性MF患者中均显示出令人瞩目的临床前和临床疗效。在此，我们回顾导致非格司亭获批的临床前和临床试验，以及正在进行的后期试验。我们强调了关于非格司亭临床应用的几个尚未得到解答的领域。我们讨论了非格司亭的局限性，并阐述了研究不足且需要进一步临床评估和研究的领域。非格司亭的获批极大地扩充了MF患者极为有限的治疗手段。
