编者按：骨髓纤维化（MF），包括原发性MF、真性红细胞增多症转化后MF及原发性血小板增多症转化后MF，是一种克隆性干细胞疾病，具有急性白血病转 化的倾向。异基因干细胞移植是治愈MF的唯一方法，但其开展受到多种因素的局限。近年来，JAK2抑制剂的出现使该疾病在治疗上获得了重大进展。在第57届美国血液协会（ASH）年会上，美国纽约西奈山医学院John O. Mascarenhas教授针对目前MF新型靶向治疗和研发进行了专题报告。会后，本刊特邀Mascarenhas教授进行了专访。

JAK2抑制剂的作用机制及疗效研究

　　在JAK2抑制剂设计之初，研究者认为只有携带JAK2突变的骨髓纤维化（MF）患者有治疗反应。但目前的研究结果显示，MF患者对JAK2抑制剂的应答与JAKV617F突变状态无关。JAK2突变是影响JAK-STAT信号途径的驱动突变之一，随着新的研究不断深入，人们发现MPL突变和钙网蛋白（CALR）突变也是JAK-STAT信号途径的重要的驱动突变，可导致JAK-STAT信号途径活化上调。Mascarenhas教授认为这或许可以解释为何JAK2抑制剂与JAK2突变状态无关。

　　Initially， when the drug development of JAK inhibitors was happening， it was presumed that only the mutated JAK carrying patents would respond to the drug. It turns out that patients respond irrespective of their JAK2 V617F mutation status. That is because the JAK2 mutation is only one driver mutation that upregulates JAK-STAT signaling. It is now recognized that MPL mutations and calreticulin (CALR) mutations are also considered driver mutations， all of which appear to somehow upregulate the hyperactivity of the JAK-STAT signaling. Therefore， JAK inhibitors seem to work regardless of the mutational status.

　　人们在长期随访中发现，JAK2抑制剂芦可替尼（Ruxolitinib）对于改善症状、缩小脾脏非常有效。一项中位随访3年的数据显示，一半的MF患者仍维持治疗，另一半的患者已脱离治疗，其原因包括药物的不良反应、出现疾病进展、以及其他原因不接受治疗。事实上，该药在疗效的持续时间上尚未明确，患者是否可以获得持续缓解，这点是目前临床研究所关注的。当然，这也可能因人而异，随着治疗时间的延长，某些患者的治疗反应将会消失，需要转入其他治疗。COMFORT-II研究的随访结果显示，小部分MF患者的骨髓纤维化程度存在下降，但确切原因尚不清楚；几例患者的分子负荷有明显下降，但大部分患者却没有这种明显的治疗反应。

　　综上所述，Mascarenhas教授认为未来还需进一步明确疾病的分子发生机制和病理生物学研究。虽然目前我们专注于JAK2抑制剂的单药治疗，但将来采用多途径的联合治疗会是必然趋势。

　　What we have found with ruxolitinib， particularly with the long-term follow-up， is that it is a highly effective drug in improving symptom burden and reducing spleen. The median follow-up of three years that has been presented and published showed that about 50% of patients remained on the study drug and half came off for various reasons that included adverse events， disease progression and withdrawal of consent. We know the drug is effective but the question is how long is it effective for individuals. For some patients， they start to lose responsiveness over time and need to move on to other therapies. The drug palliates many of the symptoms of the disease， but is not necessarily a drug that is going to put a patient into a long-lasting remission. That is really where the focus of clinical research is today. We have some evidence from some of the longer term follow-up from the COMFORT-II study that there is a subset of patients who do have downregulation of the fibrosis in the bone marrow， but that is not the case in the majority of patients. We don’t know why those patients see that response. There are a few patients who report significant reductions in their molecular burden but the majority of patients do not. So there is still a lot of work to be done to understand the molecular underpinnings and the pathobiology of this disease and much of that is now focused on other JAK inhibitors and on combinations of therapies that try to target the malignant hematopoietic stem cell.

JAK2抑制剂与造血干细胞移植

　　对于骨髓纤维化患者来说，造血干细胞移植（HSCT）是唯一提供潜在治愈可能的治疗方法。但在许多国家这种治疗方法只限于DIPSS评分中高危的患者，JAK2抑制剂的作用与移植之间的关系仍需进一步研究。目前已有一些研究正在进行中，Mascarenhas教授介绍了他们正在开展的一项临床试验，旨在比较在减低剂量的异基因干细胞移植前给予2个月的JAK2抑制治疗的效果。这项研究依据的假说是JAK2抑制剂能缩小脾脏、改善症状以及减少炎症因子；而植入的疗效与脾脏缩小有关，移植对死亡率的改善与一般状态改善有关，移植物抗宿主病的发生率及强度的下降与机体内炎症因子的下降有关。此外，移植后JAK抑制剂的应用也是目前临床研究中一大热点。

　　Hematopoietic stem cell transplantation is the only modality that offers the potential for cure for myelofibrosis patients. In this country， it is restricted to patients in the intermediate- to high-risk category according to the DIPSS score. The role of JAK inhibition in relation to transplant is still under investigation. There have been some abstracts in publications and ongoing clinical trials. For example， one of our clinical trials within the MPDRC (Myeloproliferative Disorders Research Consortium) is looking at two months of intensive JAK2 inhibition immediately prior to reduced intensity conditioning allogeneic stem cell transplantation. The hypothesis behind JAK inhibition in myelofibrosis is that a reduction in splenomegaly， improvement in symptoms and the reduction in inflammatory cytokines would lead to improvement in engraftment due to reduction of splenomegaly， improvement in transplant mortality due to an improvement in performance status and perhaps a reduction in the incidence and intensity of graft versus host disease due to downregulation of inflammatory cytokines. Those are hypotheses that have not yet been clearly demonstrated and are still under investigation. Additionally， the use of JAK inhibition post-transplant is another area of active clinical investigation.

MF新型靶向治疗药物

　　目前，芦可替尼是唯一被FDA批准的MF靶向治疗药物，仍有很多药物正在研发中。现有两种药物正在进行III期临床试验，一个是JAK2/FLT3抑制剂Pacritinib，PERSIST-1和PERSIST-2二项临床研究最终可能促使该药获得FDA批准。PERSIST-1试验结果最先报道于2015年美国临床肿瘤学会（ASCO）年会上，研究结果证实Pacritinib对缩小脾脏、改善症状效果显著。值得一提的是，这研究显示该药对血小板<50×10⁹ /L的患者疗效更佳，这一点弥补了芦可替尼仅适用于血小板>50×10⁹ /L的患者的空白。PERSIST-2研究主要针对的人群是血小板<100×10⁹ /L的患者，这也将是一个重要的研究。

　　另一个新药是JAK1/JAK2抑制剂Momelotinib。早期I/II期临床研究显示该药对于输血依赖患者，贫血治疗反应以及脱离输血依赖的比率约70%。目前III期临床研究正在进行，有望获得与前期同样的治疗反应率，使该药正式成为同类药中的一员。此外，还有其他的JAK抑制剂如Fedratinib，不过该药因其神经毒性已退出临床研究；还有一些药物仍在早期研究中，例如NS-018化合物。

　　There are a number of drugs under clinical development for myelofibrosis. The only FDA approved drug is ruxolitinib. However， there are two drugs that are furthest along in phase III testing. One is pacritinib. PERSIST-1 and PERSIST-2 are trials hopefully leading to the approval of that drug. PERSIST-1 is a positive study that was reported American Society of Clinical Oncology (ASCO) meeting in June this year and demonstrated the drug is very effective in reducing spleens and improving symptoms. It is a JAK2/FLT3 inhibitor which is different from ruxolitinib which is a JAK1/JAK2 inhibitor. The most exciting thing about that study was that for patients with low platelets (<50000) it was particularly effective and that is a clinically unmet need that ruxolitinib doesn’t currently address because the FDA approval allows for platelet levels >50000. That is an exciting turn of events and the PERSIST-2 study that is devoted to looking at patients with platelets <100000 will be an important study. Momelotinib is a JAK1/JAK2 inhibitor， similar to ruxolitinib， but in the early phase I/II studies has shown anemia responses and transfusion independence in approximately 70% of transfusion dependent patients at baseline. The ongoing phase III studies will hopefully bear out the same response and that would be a welcome addition to the JAK2 inhibitor class of drugs. There are a number of other JAK inhibitors like fedratinib (which is no longer in clinical development because of the emergence of neurotoxicity) and others that have been left behind and others that are still being tested in early phase studies， for example， the NS-018 compound.

　　除外靶向信号通路的抑制剂，还有二类药物值得一提。一种是端粒酶小分子抑制剂Imetelstat，其相关临床研究发表在NEJM杂志，显示该药具有很强的活性，可获得完全分子反应和骨髓组织病理学反应，是非常有前景的药物。目前，有关药物公司正计划开展II期研究以进一步评估其作用。另一种抗纤维化药物是PRM-151，它是穿透素2的类似物，其II期临床研究的初期结果显示，可使一半以上的患者骨髓纤维化程度降低一个等级，同时还能提高血红蛋白和血小板计数。为了进一步评估该药治疗骨髓纤维的有效性以及极低的毒性，全球多中心第二阶段试验即将启动。

　　Two more points of interest are worth mentioning. There is a drug called imetelstat which is a small molecule inhibitor of telomerase. There was a pilot study that was presented and published in the New England Journal of Medicine by Dr Tefferi， which showed a very strong signal of activity including complete molecular responses and bone marrow histopathologic responses. This is a very interesting compound and a very innovative therapeutic response that will be evaluated in the phase II setting by the Jackson pharmaceutical company. The other drug to mention is PRM-151. This is an antifibrotic drug. It is a pentraxin-2 analog and has been shown in the first stage of the phase II study to have the ability to reduce bone marrow fibrosis by at least one grade in about half the patients treated. It also shows improvements in hemoglobin and platelet counts. To further evaluate the efficacy of this innovative approach to treating myelofibrosis patients， which appears to not have a toxicity issue， the multicenter global second-stage part of the study will be opening.

专家简介

　　John O. Mascarenhas，MD，MS  美国纽约西奈山医学院副教授，恶性血液肿瘤临床研究员，主要从事骨髓增殖性肿瘤的转化医学研究，参与多项骨髓纤维靶向治疗新物的临床试验，已发表文章64篇。