Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, Box 1079, One Gustave L Levy Place, New York, NY, 10029, USA.
Curr Hematol Malig Rep. 2022 Oct;17(5):140-154. doi: 10.1007/s11899-022-00671-7. Epub 2022 Aug 19.
To discuss the current treatment paradigm, review novel targets, and summarize completed and ongoing clinical trials that may lead to a paradigm shifts in the management of myelofibrosis (MF).
In addition to the recent approval and ongoing late-stage development of multiple novel JAK inhibitors, recent clinical studies demonstrate therapeutic potential of targeting multiple alternate proteins and pathways including BET, MDM2, telomerase, BCL2, LSD1, PI3K, SMAC, and PTX2 in patients with MF. MF is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells and bone marrow fibrosis often causing cytopenias, extramedullary hematopoiesis resulting in hepatosplenomegaly, and increased pro-inflammatory cytokine production driving systemic symptoms. A significant proportion of morbidity and mortality is related to the propensity to transform to acute leukemia. Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, due to the high associated mortality, this treatment is not an option for the majority of patients with MF. Currently, there are three targeted Food and Drug Administration (FDA)-approved therapies for MF which include ruxolitinib, fedratinib, and pacritinib, all part of the JAK inhibitor class. Many patients are unable to tolerate, do not respond, or develop resistance to existing therapies, leaving a large unmet medical need. In this review, we discuss the current treatment paradigm and novel therapies in development for the treatment of MF. We review the scientific rationale of each targeted pathway. We summarize updated clinical data and ongoing trials that may lead to FDA approval of these agents.
讨论当前的治疗模式，回顾新的靶点，并总结已完成和正在进行的临床试验，这些试验可能会导致骨髓纤维化（MF）治疗模式的转变。
除了最近批准的和正在进行的多种新型 JAK 抑制剂的后期开发外，最近的临床研究表明，靶向多种替代蛋白和途径的治疗潜力，包括 BET、MDM2、端粒酶、BCL2、LSD1、PI3K、SMAC 和 PTX2，在 MF 患者中具有治疗潜力。MF 是一种骨髓增殖性肿瘤，其特征是髓样细胞的克隆性增殖和骨髓纤维化，常导致细胞减少症、骨髓外造血导致肝脾肿大，以及促炎细胞因子产生增加导致全身症状。发病率和死亡率的很大一部分与向急性白血病转化的倾向有关。异基因造血干细胞移植是唯一的治愈性治疗方法；然而，由于相关死亡率高，这种治疗并不是大多数 MF 患者的选择。目前，有三种经美国食品和药物管理局（FDA）批准的 MF 靶向治疗药物，包括鲁索替尼、fedratinib 和 pacritinib，均属于 JAK 抑制剂类。许多患者无法耐受、无反应或对现有治疗产生耐药性，这就产生了大量未满足的医疗需求。在这篇综述中，我们讨论了 MF 治疗的当前治疗模式和正在开发的新疗法。我们讨论了每个靶向途径的科学原理。我们总结了更新的临床数据和正在进行的试验，这些试验可能会导致这些药物获得 FDA 批准。
