美国M. D安德森癌症中心白血病系 Susan Mary O’Brien教授

　　Oncology Frontier: The combination of Idelalisib and Rituximab significantly improved progression-free survival (PFS)， response rate， and overall survival among patients with relapsed CLL and who are less able to undergo chemotherapy. Compared with Ibrutinib what’s your recommendation about how to choose a therapy for CLL?

　　《肿瘤瞭望》：对于复发和不适于化疗的慢性淋巴细胞白血病患者(CLL)，Idelalisib和利妥昔单抗联合应用可显著改善其无进展生存期、缓解率以及总生存期。与Ibrutinib相比，您对于CLL的治疗方案选择有何建议？

　　Dr O’Brien: Well of course right now， at least in the United States， Ibrutinib is the only drug approved. We are expecting the combination of Idelalisib and Rituximab to be approved by the FDA sometime later this year based on the exact data that you were talking about. We will be in the lucky position of having 2 excellent B-cell receptor inhibitors that can be used to treat the disease.

　　I think at this point it’s really hard to make a recommendation for one over the other except that one thing we do know is that patients on warfarin， the blood thinner， are excluded by the package insert from receiving Ibrutinib. So in terms of the patient eligibility in choosing a drug， a patient who is on a blood thinner might be someone you would choose for the Idelalisib.  I think at this point it is too early， there are no head to head comparisons， we just know they are both very effective regimens.

　　O’Brien博士：目前，至少就美国而言，Ibrutinib是唯一被批准的药物。基于你之前所提到的研究的准确数据，我们期待在年内Idelalisib联合利妥昔单抗能够被FDA批准。我们很庆幸，因为这样就会有两种有效的B细胞受体抑制剂可以用于治疗CLL。

　　目前很难在这两种药物之间做出推荐，除了口服抗凝药华法林的患者--依据Ibrutinib的药品说明书可将其排除在外，这类患者推荐应用Idelalisib。因为目前尚无针对这两种药物的头对头比较研究，大家只知道二者均为非常有效的治疗方案，因此我认为现在下结论还为时过早。

　　《肿瘤瞭望》：所以，如果FDA批准，似乎对于华法林的毒性我们需要特别加以注意。

　　O’Brien博士：这仅是对于ibrutinib而言，而idelalisib则无需注意。

　　Oncology Frontier:  So the targeted drugs are increasing in popularity. Do you think that the targeted therapy would become a main method for treating CLL at some point?

　　《肿瘤瞭望》：由于靶向治疗越来越受欢迎，您是否认为某一天靶向治疗将会成为CLL患者的主要的治疗方案？

　　Dr O’Brien: I think we all believe that in the long run it will. My own bias is it’s probably not going to be single agents and the reason I say that is we are not seeing complete remission so far in a substantial number with any of these agents. We would like to get away from chemotherapy， both because of the short and the long term toxicity， but we do need to be careful because we have presented data from MD Anderson that after 6 cycles of FCR if a patient has a mutated IGVH gene， and that’s probably about 40% of people who get treated， their progression free survival at 10-14 years is about 60%. So， now they got 6 cycles of chemo and there is myelosuppression and infections but they are done. They’re not taking a pill and they are not on continuous therapy and they’re out 10-14 years later with no evidence of disease.

　　So， I think we have to be cautious， is that a cured fraction? I would be careful about saying that， I certainly think you would agree that 6 months of therapy followed by 12 years of remission is not something you want to just dump down the drain.

　　So we have to be careful about balancing， in a certain subset， not all comers， this fabulous long term result with chemo and maybe potential for cure in a certain subset versus moving to the targeted therapies. Again I’m mostly talking about single agents because right now there’s no combination targeted therapies. But with the single agents we see so few CRs that I’m a bit skeptical that you’re going to produce that kind of long term result. But there are certainly patients where we do very poorly with chemoimmunotherapy where I’d be happy to drop chemotherapy tomorrow and the most obvious group are the patients with 17P deletions who we know fare poorly with chemo-based regimens. And then another group， which is a substantial fraction of the population， is older patients or patients with co-morbidities where you’re not worried about what’s there 14-year progression free survival if they are starting at the age of 75 and you want to use a kinder， gentler therapy.

　　So I think there are subsets where we will very quickly move away from chemo and some subsets where we have to be more cautious.

　　O’Brien博士：我想大家都相信未来一定如此。我个人的见解是靶向药物可能不会是单一用药，之所以这样讲是由于目前已有大量患者接受这些药物治疗，但未观察到完全缓解。化疗的短期和长期的毒性是我们想要摆脱化疗的主要原因。目前MD安德森癌症中心的数据显示，IGVH基因突变患者经过6个疗程的氟达拉滨联合环磷酰胺及利妥昔单抗（FCR）治疗后（约有40%的患者接受治疗），10~14年的无进展生存率约占60%。这意味着什么呢？接受6个周期的化疗，尽管出现了骨髓抑制和感染，但是能够控制，患者停止治疗10~14年，仍没有疾病迹象。

　　因此，我认为我们应该谨慎一些，这是否意味着这些患者得到了治愈？对此我会有所保留。你一定也会认可经过6个月的化疗之后缓解12年并不等于万事大吉。

　　所以我们要谨慎地来平衡。对于特定的人群，而非所有患者，这个惊人的化疗的长期结果也许意味着治愈，而不需要接受靶向治疗。再次，我主要针对的是单一用药，因为目前尚无联合方案。单药治疗几乎没有完全缓解病例，因此我对得到这样的远期结果有些质疑。的确有部分患者对化疗免疫治疗应答不佳，对这类患者今后我很愿意放弃化疗。最显著的一类患者即存在17q缺失的患者，化疗效果很差。另外一类为数众多的患者是老年患者和有共患疾病的患者，如果他们的年龄是75岁，你不会考虑14年的无进展生存期问题，而是会选择比较温和、安全的治疗方案

　　因此我认为，部分患者将很快不再采用化疗，但部分患者需要谨慎些。

　　Oncology Frontier: The elderly patients， you kind of touched on this for CLL， which combined therapies might be the most suitable for them?

　　《肿瘤瞭望》：对于年长的患者，何种治疗方案更适合他们？

　　Dr O’Brien: Yes. I think so. Because again it depends on what your end point is. In a young fit patient our end point is trying to get that remission to be as durable as possible，if not cure the patient. And why is a durable remission important? Because when people are in remission they usually have a very good quality of life and they are doing well and they’re not requiring more therapy.We know that in a 75 year old， as I just said， the expected survival is probably not going to be 15 years for the patient. So the end point probably becomes not MRD negativity or long term progression free survival， but negotiating the toxicity that you would normally get with chemo.

　　O’Brien博士：这取决于你的终点。在年轻的合适的患者，如果不能治愈，我们的目的是试图使其尽可能获得持久缓解。为什么一个持久的缓解如此重要？因为获得缓解后，患者通常有较好的生活质量并且他们能够维持，不需要更多的治疗。而对于75岁的患者，就如我刚提到过的他们的预计生存期可能不到15年。因此，治疗终点可能不是MRD（微小残留病灶）阴性或长期无进展生存，而是减少通常因化疗产生的毒性。