<International Hepatology>: Imatinib is a drug used to treat certain types of cancer including chronic myeloid leukemia.  By far how do you assess its performance in treatment of CML?

　　《肿瘤瞭望》：您是如何评价伊马替尼在治疗慢性髓性白血病的作用？

　　Prof.Mesa：Imatinib is a watershed drug in the therapy of cancer.  As a targeted therapy for CML Chronic Phase has been one of the most effective single agent oral therapies for any cancer that has ever been developed.  In results of the watershed mechanistically for the development of other tyrosine kinase inhibitors which have even a greater impact on CML， including

　　Nilotinib， Dasatinib， Bosutinib， and eventually Ponatinib.  Indeed， now there are five approved tyrosine kinase inhibitors of which there are various international guidelines regarding their timing and sequence.

　　Mesa教授：伊马替尼是在肿瘤治疗中具有里程碑意义的药物。作为慢性粒细胞白血病慢性期的靶向治疗，伊马替尼的有效性优于之前任何肿瘤单一口服药物。因其疗效确切，其他对慢粒更有效的酪氨酸激酶抑制剂也逐渐被研发出来，包括Nilotinib、Dasatinib、Bosutinib和Ponatinib。事实上，目前这五种酪氨酸激酶抑制剂已被不同的国际指南推荐，用于不同时机和不同序列的慢性粒细胞白血病。

　　<International Hepatology>: Disordered signaling for the JAK stat pathway is a hallmark of myeloproliferative neoplasms.  In the future will JAK inhibitors be used to treat myeloid malignancy and what will be future targeting agents of myeloid malignancies?

　　《肿瘤瞭望》：您能谈谈JAK2抑制剂在骨髓增殖性肿瘤中的应用前景吗？您认为未来靶向治疗髓细胞恶性肿瘤的药物是什么？

　　Prof.Mesa：The JAK inhibitors， currently Ruxolitinib and other agents in development， such as Pacritinib and Momelotinib， are incredibly impactful in myelofibrosis， with Phase III data from the COMFORT1 and COMFORT2 studies for myelofibrosis clearly demonstrating significant impact in terms of improvement in splenomegaly symptoms and even survival.  Ongoing Phase III studies with Pacritinib and Momelotinib are ongoing as frontline therapies for patients with myelofibrosis.  Ruxolitinib has also demonstrated activity and significant benefit in the Phase III study for patients with second line therapy for polycythemia vera， demonstrating improvements in hemoglobin and hematocrit control， improvement in splenomegaly， and improvement of symptoms.  JAK inhibitors are being tested in myelodysplastic syndrome as well as MPN MDS overlap syndromes， although these data are not fully elucidated.

　　Mesa教授：JAK通路抑制剂，当前已有的药物（如Ruxolitinib）和其他在研的药物（如Pacritinib、Momelotinib）都对骨髓纤维化治疗非常有效。骨髓纤维化COMFORT1 和 COMFORT2 III期的临床试验显示，JAK通路抑制剂对于脾大甚至生存都有很好的效果。Pacritinib和Momelotinib作为骨髓纤维化一线用药的III期临床研究正在进行。III期临床试验显示了Ruxolitinib在真性红细胞增多症患者的二线治疗中的有效性和很好获益：血红蛋白和红细胞压积的改善、脾大和临床症状的缓解。JAK通路抑制剂治疗MPN MDS重叠综合征患者的疗效，目前尚不清楚。

　　<International Hepatology>: As the current clinical trials of MPNs are evolving from single agent to combination strategies， what are these combination strategies at present?

　　《肿瘤瞭望》：目前骨髓增殖性肿瘤的综合治疗手段有哪些？

　　Prof.Mesa：The combination strategies for myeloid malignancies build on a base of JAK inhibition as the main approved therapy for particularly myelofibrosis.  They exist along various themes.  The first theme is in combination with agents which might help to improve anemia， including Azacytosine， Decitabine， erythropoietin， pomalidimide， lenalidimide.  Then there are combination studies looking at combinations of JAK inhibition along with other agents which may impact the fibrosing process， including hedgehog inhibitors， locks O2 antibodies， and PI3 kinase inhibitors.  Finally， there are combinations with other strategies which have shown activity in a single agent， such as the histone deacetylase inhibitor panobinostat.  All of these combination studies are early enough in development.  It is not clear which will be superior.

　　Mesa教授：髓系恶性肿瘤联合用药的策略是基于JAK通路抑制剂作为改善骨髓纤维化的主要治疗手段。联合用药有不同的方案：①联合可能有助于改善贫血的药物，如氮胞嘧啶、地西他滨、红细胞生成素、泊马度胺、来那度胺。②联合可能影响纤维化进程的药物，如hedgehog抑制剂、locks O2 抗体和PI3激酶抑制剂。③联合其他已经显示出单药有效性的药物，如组蛋白去乙酰化酶抑制剂——帕比司他。这些联合用药目前都处于早期研究阶段，优越性尚不清楚。

　　<International Hepatology>: Can we monitor the effective treatment therapy for myeloid malignancies and how?

　　《肿瘤瞭望》：在骨髓增殖性肿瘤中是否可以实现靶向治疗后的监测？如何进行检测？

　　Prof.Mesa：The response criteria for myeloid malignancies continue to evolve and truly are broken down disease by disease specific.  The goal for chronic myeloid leukemia is a very high bar with the achievement of major molecular response， complete molecular response as being the goal of therapy.  In patients with MPNs we utilize a combination of the international working group and ELN response criteria for PV， ET， and myelofibrosis that have various thresholds of response， including complete and partial responses as well as clinical improvement.  Response criteria for myelodysplastic syndrome overlap with these but are slightly different with differing goals such as improvement of cytopenias and delay in transformation to acute myeloid leukemia.  The myeloid malignancies have many areas of overlap; however， their phenotypes remain different.  The benefits the therapies have given them remain on a spectrum and on this basis there still is much individualization which is required regarding the utilization of therapy as well as the assessment of its response.

　　Mesa教授：髓系肿瘤的疗效标准一直在改变，不同疾病其标准也不一样。慢性粒细胞白血病的治疗目标要求非常高，要达到主要分子水平和完全分子水平的缓解。对于MPN患者，我们采纳国际工作组和欧洲白血病网络对于真性红细胞增多症、原发性血小板增多症和骨髓纤维化的疗效标准，包括完全缓解、部分缓解和临床改善。骨髓增生异常综合征的疗效标准与此有重叠，但在血细胞减少和延迟向急性髓系白血病转换的时间上有所不同。髓系肿瘤的标准有很多相同之处，但是其表型各不相同。治疗的获益因疾病谱、个体化治疗的情况以及疗效的评估而不同。