美国加利福尼亚大学欧文分校Susan Mary O’Brien 教授访谈

　　TKI在费城染色体阳性急性淋巴细胞白血病（PH+ALL）中的应用

　　酪氨酸激酶抑制剂（TKI）在治疗慢性髓系白血病（CML）中有广泛应用。随着新一代TKI的出现，有许多关于一、二代TKI在CML治疗中的临床随机对照研究。目前的研究认为，二代TKI在CML中更具有潜力。与之相比，在PH+ALL患者中，现有的数据绝大多数还是一代TKI伊马替尼（Imatinib）的应用，仍没有比较一、二代TKI疗效的临床研究。依照CML中的经验，可能大多数人会默认使用二代TKI治疗ALL。

　　现在，我们开始逐渐看到关于尼洛替尼（Nilotinib）、达沙替尼（Dasatinib）的研究数据，还有MD安德森癌症中心关于比较泊那替尼（Ponatinib）与hyper-CVAD方案治疗PH+ALL的研究结果也非常引人注目。其中一个主要的问题是，有研究表明泊那替尼增加了CML患者的动静脉血栓形成事件。个人认为，这可能与泊那替尼的高使用剂量相关。目前已有研究旨在考察将45 mg的标准剂量降低到30 mg的效果，如果其研究结果证实降低剂量后该药仍然有效并且安全，那么泊那替尼将是在PH+ALL治疗中最具有前景的TKI药物。

　　Prof. O’Brien: Unlike in CML， we don’t have any randomized trials in Ph-positive ALL comparing first-generation or second-generation TKIs. Based on the understanding that the second-generation are more potent in CML， I think most people have defaulted to using second-generation TKIs in ALL， although most of the published data up until now is with imatinib. We are， however， starting to see published data with both erlotinib and dasatinib. There is some very interesting MD Anderson data with ponatinib. One of the problems with ponatinib is that in CML there were increased arterial and venous thrombotic events and I think the feeling with that drug is that the dose is too high and there are some studies now looking at a lower dose in CML (30mg) rather than the standard 45mg. If it becomes clear that that is a safe and effective dose， we may see a move toward ponatinib in the future because the MD Anderson data with hyper-CVAD and ponatinib is by far the best data out there for Ph-positive ALL with a TKI.

　　PH+ALL患者选择干细胞移植的标准

　　从历史上说，PH+ALL过去被认为是最难治的白血病之一。这并非因为患者在治疗后总体上不能得到缓解，而是患者基本上都将面临ALL复发。因此从本质上说，如果不接受干细胞移植，这些患者无法治愈。所以，PH+ALL治疗的意图就是让每位患者都能做干细胞移植。然而在20~30年前，由于干细胞移植都是清髓性移植，不适合年老患者，因此仅推荐年轻患者进行移植。现今，我们可以通过减低强度预处理来为年老患者进行移植，并且我们发现，决定患者能否进行移植的因素主要取决于患者的身体状况和合并症，并不仅限于部分患者。

　　Prof. O’Brien: Historically， Ph-positive ALL was considered one of the worst leukemias and that was not because people generally didn’t get into remission， but because they all relapsed. Essentially， without a stem cell transplant， there really was no cure. The intent then was to get everyone to stem cell transplant， although twenty or thirty years ago， that really only allowed younger patients a curative option because all of our transplants then were myeloablative and simply weren’t available to older patients. Now we have the possibility of doing reduced intensity transplants in older patients and I don’t think people necessarily choose one over the other， they choose on the age and comorbidities of the patient.

　　从临床试验中我们可以看出，自体干细胞移植与异基因干细胞移植同样有效。然而在大多数的研究中，患者都经过伊马替尼维持治疗一段时间后再进行自体干细胞移植。可见伊马替尼维持治疗在整个治疗过程中的重要作用。而我们将面临的问题是，是否伊马替尼维持治疗后仍有必要进行移植。这方面我们仍不清楚。

　　Prof. O’Brien: If you look at some of the trials where patients got allo- or auto- (and usually the reason they got auto- was simply because they didn’t have a suitable donor)， in several trials， the patients who received auto- did just as well. However， in most of the trials， they didn’t just get an auto-; they got imatinib maintenance for some extended period of time after that. Again， this raises the question if imatinib maintenance is the important part of it， do you need to actually have the auto-transplant? How important is the imatinib maintenance/auto- combination? That is data that is not entirely clear.

　　获得完全分子学缓解后是否仍需移植？

　　截止目前，如果患者有合适的骨髓捐献者，多数治疗中心都会为患者做干细胞移植。并且，已有大量的数据表明患者的术后应答良好。如果患者通过化疗和TKI治疗后获得完全分子学缓解，也许不必再行移植。然而，目前并没有这方面的随机对照研究。一个好的消息是，美国大型肿瘤合作小组将进行相关研究，这将是一个非常重要的项目。

　　Prof. O’Brien: Up until now， if the patient had a donor， most centers would include transplant. There is emerging data that patients have a really good response. By that I mean a major molecular response with complete molecular remission after chemotherapy and a TKI. These people with such a great response may be the ones that don’t need to have a transplant. Is there any randomized clinical trial answering that question? As of now， no. The good news， however， is that the American intergroup in the US， made up of all the large medical oncology cooperative groups is about to embark on a large randomized trial in Ph-positive ALL where the final question being asked is， if you have a patient with a complete molecular response， do they need a transplant? The randomization will be to transplant with the best suitable donor or not to have a transplant but continue on TKI maintenance. That will be a very important trial. Some may think that that trial will take a really long time to do if you want to look at survival because you are taking the best group， the ones with complete molecular response. But there will be a surrogate endpoint of， rather than waiting for the potential years it would take to get an answer on survival， we will be looking at time to molecular recurrence as an endpoint， so that should give us an answer in a more timely fashion.

　　总之，PH+ALL治疗中的一个重要问题是：是否每位患者都需要干细胞移植，自体干细胞移植或者异基因干细胞移植。尤其关键的是，已获得良好分子学应答的患者是否需要移植。目前虽然尚未有临床试验的数据，但是未来必将有明确的答案。依据目前的研究现状，本届ASCO年会上所呈现的研究结果表明，的确有患者在维持治疗后获得了满意的疗效。

　　Prof. O’Brien: So in summary， an important question in Ph-positive ALL is whether we still need transplants in everybody， either allo- or auto-transplant. In particular， do we need transplants in patients who have a very good molecular response? So far， there are no randomized trials， but there will be one. However， looking at aggregate data from trials， which is what I am talking about here at ASCO， there are clearly cohorts of patients who don’t have an allo- or an auto- and who continue on maintenance and who do quite well. We know there is a subset that potentially have a curefraction there， but what we don’t know without the randomized trial is would we actually cure more of those patients with a transplant， or is transplant overkill in a population that can do well with continued TKI maintenance?