Gregory Stephanie A, Mesa Ruben A, Hoffman Ronald, Shammo Jamile M
Department of Internal Medicine, Rush University Medical Center/Rush University, Chicago, Illinois, USA.
Clin Adv Hematol Oncol. 2011 Sep;9(9 Suppl 22):1-16.
Myelofibrosis (MF) is a life-threatening clonal stem cell malignancy characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. The term "MF" encompasses primary myelofibrosis (PMF) as well as 2 other phenotypically similar malignancies: post-polycythemia vera (PV) MF (PPV-MF) and post-essential thrombocythemia (ET) MF (PET-MF). The World Health Organization classification system for myeloid malignancies recognizes PMF, PV, ET, and chronic myeloid leukemia (CML) as the "classic" myeloproliferative neoplasms (MPNs). Patients with low- or intermediate-1-risk disease have a median survival of 6-15 years, in contrast to those with intermediate-2- or high-risk disease, which is associated with a considerably worse prognosis. Following transformation into (secondary) acute myeloid leukemia (AML), the prognosis of MF is even worse, with a median survival of 3 months or less. Due to the heterogeneous nature of MF, the diagnosis and treatment of this malignancy can be challenging. At present, the only treatment that can be applied with curative intent is allogeneic stem cell transplantation (SCT), whereas no other specific therapies exist that are approved by the US Food and Drug Administration (FDA) for MF. Since most patients with MF appear not to be eligible for allogeneic SCT, patients are often treated by conventional "older" drugs such as androgens and hydroxyurea (HU; hydroxycarbamide), with the principal objective being palliation. Following the establishment of a causal role of a specific mutation in the Janus kinase type 2 (JAK2) gene, namely JAK2V617F, in the molecular pathogenesis of MPNs in 2005, many efforts have been directed towards the development of novel JAK2 (including JAK1/JAK2) inhibitors. Other investigative approaches include immunomodulatory agents, histone deacetylase inhibitors, hedgehog inhibitors, and others. Recently, the positive results of the first in class of the JAK1/JAK2 inhibitors, ruxolitinib (formerly INCB18242), from 2 large phase III studies were presented and are discussed herein.
骨髓纤维化（MF）是一种危及生命的克隆性干细胞恶性肿瘤，其特征为进行性骨髓纤维化和无效造血。术语“MF”包括原发性骨髓纤维化（PMF）以及其他两种表型相似的恶性肿瘤：真性红细胞增多症后（PV）骨髓纤维化（PPV-MF）和原发性血小板增多症后（ET）骨髓纤维化（PET-MF）。世界卫生组织的髓系恶性肿瘤分类系统将PMF、PV、ET和慢性髓系白血病（CML）识别为“经典”骨髓增殖性肿瘤（MPN）。低风险或中危-1疾病患者的中位生存期为6至15年，相比之下，中危-2或高危疾病患者的预后则要差得多。在转化为（继发性）急性髓系白血病（AML）后，MF的预后更差，中位生存期为3个月或更短。由于MF具有异质性，这种恶性肿瘤的诊断和治疗具有挑战性。目前，唯一可用于根治性治疗的方法是异基因干细胞移植（SCT），而美国食品药品监督管理局（FDA）尚未批准其他针对MF的特异性疗法。由于大多数MF患者似乎不符合异基因SCT的条件，患者通常接受传统的“老药”治疗，如雄激素和羟基脲（HU；羟基脲），主要目的是缓解症状。2005年确定了2型Janus激酶（JAK2）基因中的特定突变JAK2V617F在MPN分子发病机制中的因果作用后，人们致力于开发新型JAK2（包括JAK1/JAK2）抑制剂。其他研究方法包括免疫调节剂、组蛋白去乙酰化酶抑制剂、刺猬信号通路抑制剂等。最近，首个JAK1/JAK2抑制剂鲁索替尼（原INCB18242）在两项大型III期研究中取得了阳性结果，本文将对此进行介绍和讨论。
