Bose Prithviraj, Masarova Lucia, Verstovsek Srdan
Department of Leukemia, MD Anderson Cancer Center.
Rinsho Ketsueki. 2019;60(9):1176-1185. doi: 10.11406/rinketsu.60.1176.
Although the Janus kinase (JAK) inhibitor ruxolitinib has long been the only drug licensed for treatment of the classic Philadelphia chromosome negative (Ph) myeloproliferative neoplasms, years of drug development efforts have begun to bear fruit with the recent approval of a novel monopegylated interferon alfa-2b, ropeginterferon alfa, for patients with polycythemia vera without symptomatic splenomegaly in Europe. Several newer JAK inhibitors (fedratinib, pacritinib, momelotinib) have shown activity in phase 3 trials in patients with myelofibrosis but have, for various reasons, not yet received regulatory approval; all these agents, however, remain in active clinical development. Many other agents with diverse mechanisms of action are being explored in clinical trials in patients with myelofibrosis, both as single agents and in combination with ruxolitinib. Besides splenomegaly and symptoms, improvement of anemia has become a new focus of drug development in myelofibrosis. Ruxolitinib appears promising also in chronic neutrophilic leukemia, where mutations in CSF3R are common. Pemigatinib, a potent and selective inhibitor of fibroblast growth factor receptor (FGFR), has shown impressive efficacy in a small registration-directed trial in patients with FGFR1-rearranged myeloid/lymphoid neoplasms. Finally, avapritinib, a highly potent and selective inhibitor of KIT, has demonstrated unprecedented response rates in patients with advanced systemic mastocytosis.
尽管多年来，Janus激酶（JAK）抑制剂芦可替尼一直是唯一被批准用于治疗典型的费城染色体阴性（Ph）骨髓增殖性肿瘤的药物，但经过多年的药物研发努力，一种新型单聚乙二醇化干扰素α-2b（罗培干扰素α）最近在欧洲获批，用于治疗无症状脾肿大的真性红细胞增多症患者，这已初见成效。几种更新的JAK抑制剂（非达替尼、帕西替尼、莫美替尼）在骨髓纤维化患者的3期试验中显示出活性，但由于各种原因尚未获得监管批准；然而，所有这些药物仍在积极进行临床开发。在骨髓纤维化患者的临床试验中，正在探索许多其他具有不同作用机制的药物，既作为单一药物使用，也与芦可替尼联合使用。除了脾肿大和症状外，改善贫血已成为骨髓纤维化药物研发的新重点。芦可替尼在慢性中性粒细胞白血病中似乎也很有前景，在这种疾病中，CSF3R突变很常见。培米加替尼是一种强效且选择性的成纤维细胞生长因子受体（FGFR）抑制剂，在一项针对FGFR1重排的髓系/淋系肿瘤患者的小型注册导向试验中显示出令人印象深刻的疗效。最后，阿伐替尼是一种高效且选择性的KIT抑制剂，在晚期系统性肥大细胞增多症患者中显示出前所未有的缓解率。
