Oncology Frontier:  The development of targeted treatments for CLL is changing the prognostic outlook for CLL patients. Can you outline some of these new therapies? 

　　《肿瘤瞭望》：CLL的靶向治疗改变了CLL患者的预后，请您列举一些代表性药物及其临床效果？

　　Dr Jones: Two drugs have been approved here in the United States in the last year that target downstream kinases from the B-cell receptor signaling， so these are B-cell receptor signaling kinase inhibitors. These drugs are targeting Bruton’s tyrosine kinase (ibrutinib) and the PI3 kinase delta isoform (idelalisib) and both have substantial activity across the genetic risk groups regardless of age or response to prior therapy. While these two drugs have entered clinical practice， I think we have a lot to learn about where they best fit in. We are still generating data about the potential for combination therapies either with or without chemotherapy to improve clinical results. We are also interested as to whether early use of these drugs either as initial therapy or in an early intervention setting could impact the natural history of the disease. Beyond that， we are already seeing the second-generation drugs in both classes as well as targeting other B-cell receptor signaling kinases that also have activity that may be more potent and may have a more favorable side effect profile because they are more specific for their kinase of interest. The last group of drugs that I think all of us are interested to see the potential of for hematology malignancies even beyond CLL， are the drugs that are modifying immune system response. We have extensive experience with monoclonal antibodies targeting cell surface markers of B-cell malignancies but the newer drugs that attempt to restore immunologic function in patients with advanced malignancies， the checkpoint inhibitors (PD-1 and PD-L1 inhibitors such as nivolumab and pembrolizumab) are very interesting for their potential to be combined with any of the new agents. The last class of drugs that is most promising in CLL involves the pharmacologic inhibition of BCL-2 which is known to be highly effective in patients with relapsed and refractory CLL with response rates that are similar to those obtained with the B-cell receptor kinase inhibitors. Interestingly， these drugs are maybe more likely to achieve complete remission with minimal residual disease. So there is a lot still to be explored with those drugs as we think about their place in therapy or in combination.

　　Jones教授：去年美国批准了2种B细胞受体酪氨酸激酶抑制剂。这些药物靶向Bruton激酶（ibrutinib）和PI3K-delta抑制剂（idelalisib），并且对于各种年龄、危险分层及前期治疗的患者都有一定的疗效。我们需要了解这两种即将广泛应用的药物。肿瘤学家们也仍然在不断地尝试其用于联合或不联合化疗对于临床结局是否有益。除此之外，已经有特异性更高的第二代B细胞受体激酶抑制剂，其对于免疫系统有作用，因而对于CLL意外的血液系统肿瘤也可能有效。B细胞表面上的marker也存在很多单抗，如PD-1和PD-L1抑制剂，这些单抗可能对机体免疫功能影响很小，如nivolumab、pembrolizumab，很有前景，也极有可能和其他新药联合应用于CLL的治疗。最后一类最有潜力的药物包括BCL-2受体抑制剂，对于复发难治的CLL效果很好，而且有可能实现仅有MRD的CR。因此对于治疗以及联合用药方面上述新药值得探索的问题是非常多的。

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