Metzger Megan, Avigan Zachary M, Vachhani Pankit, Waksal Julian, Mascarenhas John
Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Division of Hematology and Oncology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL.
Blood Neoplasia. 2024 Apr 12;1(2):100010. doi: 10.1016/j.bneo.2024.100010. eCollection 2024 Jun.
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by constitutional symptoms, progressive cytopenias, and splenomegaly. Activating mutations in the JAK/STAT pathway and cytokine dysregulation driving bone marrow fibrosis and extramedullary hematopoiesis underlie the pathobiology of MF. Although multiple JAK inhibitors are currently approved and provide significant symptom improvement, these agents do not possess disease course modifying potential. Additionally, outcomes are poor for patients who fail JAK inhibitors, highlighting the need for novel mechanism-based therapies and innovative combination strategies. Selinexor, a novel Exportin 1 (XPO1) inhibitor that blocks nuclear export, increases nuclear localization and activity of p53 and other tumor suppressor pathways and decreases cytoplasmic activation of multiple proliferative and profibrotic pathways. Selinexor currently has approved indications in multiple myeloma and lymphoma, with broad potential applications in other malignancies, although it can be limited by toxicity in some settings. Selinexor has shown clinical activity and tolerability in MF, both as monotherapy and, particularly, in combination with ruxolitinib. The collective, early phase trial data support a phase 3 randomized, registration study of selinexor and ruxolitinib in patients with MF naïve to JAK inhibitor therapy. Further work is needed to elucidate the role of XPO1 inhibition as a potential disease-modifying strategy to improve outcomes in MF.
骨髓纤维化（MF）是一种骨髓增殖性肿瘤，其特征为全身症状、进行性血细胞减少和脾肿大。JAK/STAT通路的激活突变以及驱动骨髓纤维化和髓外造血的细胞因子失调是MF病理生物学的基础。尽管目前多种JAK抑制剂已获批准并能显著改善症状，但这些药物不具备改变疾病进程的潜力。此外，对JAK抑制剂治疗无效的患者预后较差，这凸显了基于新机制的疗法和创新联合策略的必要性。塞利尼索是一种新型的核输出蛋白1（XPO1）抑制剂，可阻断核输出，增加p53和其他肿瘤抑制通路的核定位及活性，并降低多种增殖和促纤维化通路的胞质激活。塞利尼索目前已获批用于多发性骨髓瘤和淋巴瘤的治疗，在其他恶性肿瘤中具有广泛的潜在应用，尽管在某些情况下可能会受到毒性的限制。塞利尼索在MF中已显示出临床活性和耐受性，无论是单药治疗，尤其是与芦可替尼联合使用时。早期试验的总体数据支持开展一项针对初治JAK抑制剂治疗的MF患者的塞利尼索和芦可替尼的3期随机注册研究。需要进一步开展工作以阐明抑制XPO1作为一种潜在的疾病改善策略在改善MF患者预后中的作用。
