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Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis

机译：超越Raxolitinib：Fedratinib和其他肌电纤维化的突出治疗方案

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Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke’s encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.
机译：肌细胞纤维化（MF）是一种肌鳞状肿瘤，其特征，其特征在于分化骨髓细胞的克隆增殖，导致骨髓纤维化，细胞分析和髓外血液血液。 2019年底，FDA批准了高精度的JAK2抑制剂Fedratinib，用于中间体-2或高风险的初级或二级MF，使其在Raxolitinib批准的MF批准的MF批准的第二种药物，该jak1 / 2抑制剂被批准用于MF 2011年。Fedratinib的批准是基于第二阶段试验和III阶段雅加达试验，其中药物与安慰剂相比，药物显着降低了脾肿大和症状负担，包括以前用ruxolitinib治疗的一些患者。 Fedratinib的主要副作用包括贫血，胃肠道症状和肝脏转氨酶中的升高。 Fedratinib还有一个用于脑病的盒子警告，尽管这仅发生在约1％的治疗患者中，大多数最终觉得不代表Wernicke的脑病。尽管如此，建议在高危患者中监测硫胺素水平和补充。这种担忧导致了临床持续的临床持有，延迟了药物交换制造商的几年后的药物批准，突出了需要细致的调查和对药物开发中的严重但罕见的不良事件的判决，这可能最终可以预防药物批准的有利风险/效益比例。在这篇综述中，我们讨论了药代动力学数据和疗效，以及Fedratinib的临床试验的毒性结果。我们还审查了MF中的Jak抑制剂的持续试验，并探索了对Ruxolitinib难治的MF患者的未来治疗选择。

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