Patel Ami B, Vellore Nadeem A, Deininger Michael W
University of Utah Huntsman Cancer Institute, Salt Lake City, Utah.
Chief of Hematology, University of Utah Huntsman Cancer Institute, Salt Lake City, Utah.
Clin Cancer Res. 2016 Mar 1;22(5):1037-47. doi: 10.1158/1078-0432.CCR-15-0905.
The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Although these clonal disorders share certain clinical and genetic features, MF in particular is distinct for its complex mutational landscape, severe disease phenotype, and poor prognosis. The genetic complexity inherent to MF has made this disease extremely challenging to treat. Pharmacologic JAK inhibition has proven to be a transformative therapy in MPNs, alleviating symptom burden and improving survival, but has been hampered by off-target toxicities and, as monotherapy, has shown limited effects on mutant allele burden. In this review, we discuss the genetic heterogeneity contributing to the pathogenesis of MPNs, focusing on novel driver and epigenetic mutations and how they relate to combination therapeutic strategies. We discuss results from ongoing studies of new JAK inhibitors and report on new drugs and drug combinations that have demonstrated success in early preclinical and clinical trials, including type II JAK inhibitors, antifibrotic agents, and telomerase inhibitors.
经典的 BCR-ABL1 阴性骨髓增殖性肿瘤（MPN）包括原发性血小板增多症（ET）、真性红细胞增多症（PV）和骨髓纤维化（MF）。尽管这些克隆性疾病具有某些临床和遗传特征，但 MF 尤其因其复杂的突变图谱、严重的疾病表型和不良预后而与众不同。MF 固有的遗传复杂性使得这种疾病的治疗极具挑战性。药理学上的 JAK 抑制已被证明是 MPN 的一种变革性疗法，可减轻症状负担并提高生存率，但受到脱靶毒性的阻碍，并且作为单一疗法，对突变等位基因负担的影响有限。在本综述中，我们讨论了导致 MPN 发病机制的遗传异质性，重点关注新的驱动基因突变和表观遗传突变以及它们与联合治疗策略的关系。我们讨论了正在进行的新型 JAK 抑制剂研究结果，并报告了在早期临床前和临床试验中已证明成功的新药和药物组合，包括 II 型 JAK 抑制剂、抗纤维化药物和端粒酶抑制剂。
