15th International Workshop on Chronic Lymphocytic Leukaemia (iwCLL 2013)

Advances in CLL from iwCLL 2013

Professor Michael Hallek - University of Cologne, Germany
Professor Susan O’Brien, MD Anderson Cancer Center, Houston, Texas, USA
Dr Kanti Rai, Long Island Jewish Medical Center, New York, USA
Professor Jan Burger, MD Anderson Cancer Centre, Houston, Texas, USA
Professor Anders Österberg, Karolinska Hospital, Stockholm, Sweden

MH: Welcome to Cologne, to the International Workshop on CLL 2013 in an exciting meeting so far. I have the privilege to be with a number of distinguished guests and professors around me; we will have a lovely discussion about the novelties and all the innovations in CLL. With me is Professor Susan O’Brien from the MD Anderson Cancer Center, Professor Kanti Rai from New York or North Shore Long Island, Professor Jan Burger from, again, the MD Anderson in Houston and Anders Österberg from Sweden. My name is, as I said, Michael Hallek from Cologne. So we can start a good discussion about all this exciting news of the meeting and one of the questions that came up this morning was the value of chemoimmunotherapy. We started to think with all the novelties and all the novel agents this is over and we will reduce the importance of chemoimmunotherapy but all of a sudden there’s new data coming up showing that some of the patients may actually benefit. The question is, maybe Susan as somebody who is very knowledgeable in this field you want to start with it, what do you think is the current value of chemoimmunotherapy such as FCR or BR in patients with CLL, let’s say young and old and so on?

SOB: What’s clear is that everybody is excited about the new drugs but I don’t think we want to necessarily throw out the old drugs, perhaps choosing better who we know are going to benefit from those therapies. So we had some discussion about that this morning; high risk patients such as those with 17p deletion or 11q mutation/deletion don’t do as well, the unmutated don’t do as well, older patients who cannot tolerate chemoimmunotherapy, older patients with comorbidities don’t do as well. But the flip side of that is identify a cohort that does quite well such as those who are mutated trisomy 12 and those patients can have ten year progression free survival curves. There were two presentations this morning, one from MD Anderson, one from the Germans, suggesting there might even be a plateau on those curves. So I don’t think we can just rush into, dive into, the new therapies for everybody and throw out some of the benefits that we already have.

MH: So here is somebody of the same institution who was developing some of the new drugs. Many of you have participated in the trials but Jan Burger has lots of knowledge about these novel agents. Would you agree with this or say, well, the beauty of the new agents is they are less toxic, the patients are in demand, they are asking for these new drugs and they will no longer want to have chemoimmunotherapy. What’s your opinion about this?

JB: Yes, I agree there’s a little bit of hype and we have to keep in mind that these novel agents have been tested only for a relatively short period of time and we really don’t know the long-term side effects, toxicity and the long-term outcome of these patients. So I would agree with Susan O’Brien’s comments, we probably have to better define which patients benefit in the long run from chemoimmunotherapy and select those. But what is emerging is the high risk patients are doing better on these novel agents and probably the answers are going to come from these trials we are now doing in front line or relapsed where we compare novel agents, kinase inhibitors, versus chemoimmunotherapy.

MH: So then we would eventually agree, and I ask Kanti whether he does, with what Neil Kay actually concluded and what seems to be a consensus amongst the two other speakers, that there is low risk and higher risk patients and we need to consider them separately when it comes to chemoimmunotherapy.

KR: That’s exactly what Susan just also mentioned and you’re right that at this 2013 International Workshop on CLL has clearly highlighted that we are not throwing out FCR of the window but this meeting has clarified as to what particular patients are benefitting the most and where, in what circumstance we should start off with alternatives to FCR. As has been mentioned, 17p is a good case in point and that is where probably a BTK inhibitor or the Bcl-2 inhibitor or a PI3 kinase, but as Jan has mentioned, that those are very new and exciting and effective drugs but we have not followed the patients long enough to make a definitive statement. But the initial results are clearly demonstrating that in 17p if we have an alternative then we should go to that and, as we heard about allogeneic transplant which used to be considered very high for 17p, are now being questioned whether that is the best strategy in view of the new BCR inhibitors.

MH: So now Thaddeus Robert this morning also made a nice overview of the current practice with all these agents, at least in the continents and countries and even countries that can’t afford it. The next question about a totally different concept, it’s the old concept of chlorambucil and the like, like alkylators, in some parts of the world it’s still the backbone of all therapies; in others, like in the US, it’s barely used in some centres. What is your opinion about the role of these agents, alkylators, even bendamustine comes now into the game? What’s their current position in the scenario?

AO: My perspective is very Scandinavian and we’re forced to be very evidence based, that means that we still use a little bit of the old drugs in the way they are approved and in hopefully a relatively smart and cost-effective way. It means, for instance, that we are a little bit hesitant to use FCR in elderly patients because some toxicity in that population, that we have perhaps started to use R-bendamustine in elderly patients a little bit before the phase III data are available. Chlorambucil is still used in our centres in some of the elderly patients but it could be discussed, based on the phase III trials we have now with the new CD-20 antibodies, if that is the way to go or if it could be better to combine the new antibodies with more effective chemotherapeutic drugs than chlorambucil.

MH: How about you, Kanti? You have been one of the last defenders amongst the American physicians still using chlorambucil from time to time. In our days now do you still use chlorambucil?

KR: Oh yes, I am not only one of the hold-outs but I have sufficient justification that in some patients, particularly as Anders mentioned, some populations, the really elderly, the famous Hallek no-go or very slow-go patients, elderly with co-morbidities, we have to accept that our therapeutic endpoint for those patients should not be as it is for go-go patients where it is complete remission and if possible MRD negative status. In slow-go or no-go our strategy should be maintaining the quality of life of that person and reducing the tumour burden. Many people call that palliative therapy, I feel that chlorambucil is a proven agent which should be used and, as has been mentioned, in combination with either rituximab or GA101. The GA101 data are absolute exciting and very convincing that, not only in those populations, elderly and co-morbid, the German trials, there is also MRD negative CRs, that is extraordinary that one could not achieve with combining chlorambucil to rituximab. So I feel that chlorambucil is still a valid option but perhaps not as a single agent.

MH: OK. So I would have convinced you with the German data that, and just for the audience the CLL11 data, showing that both CD20 antibodies in this trial, rituximab and obinutuzumab, were actually superior to chlorambucil. Now, the question is will that eventually translate into clinical practice? I could ask anybody, I’ll ask Anders Österberg, do you think that maybe in your practice if the data comes out and it’s approved you would use that in this combination, especially for the population of the not so fit patients, the slow-go patients?

AO: Yes, this is a very good question. That example is a very good trial, it’s carefully conducted with convincing data. We have about the same, similar data, in the ofatumumab trial with chlorambucil. Both of these antibodies are, of course, more expensive than rituximab and my perspective a little bit later on, perhaps, when we will access to biosimilar rituximab with much lower cost, is it then worth the difference to gain some additional activity in this situation and is that a possibility to save money instead to have access to buy the small expensive new molecules because patients will need them as well? So it’s not an easy question to answer right now, there are so many aspects that relate, that come into this.

MH: Maybe we should discuss one point because that’s what was referred to: the MRD, minimal residual disease negativity, which has only been seen with the one combination, that is GA101, not with rituximab. As a good clinician, Susan, would you say that this is so convincing that you would use a novel antibody rather than the old one or do you think it doesn’t matter for these elderly patients?

SOB: Again you have to come back to Kanti’s point. I think seeing MRD negativity in this setting was very exciting because, as was previously noted, you don’t see it with chlorambucil, in fact you barely even get a morphologic complete remission. You don’t see it with chlorambucil and rituximab and yet you saw it at a pretty reasonable frequency here. On the other hand if what we’re talking about is having a population where all we’re really interested in is palliation then I think Anders’ point is relevant, it’s fine to use chlorambucil because it’s easy and it’s cheap but then if you use it with what’s presumably going to be a very expensive antibody just because you want to get MRD negativity, how does that fit in with palliation or keeping costs down? So there’s a little bit of a disconnect there. Perhaps a more interesting question would be if obinutuzumab can make chlorambucil this much better, what could it do with a better chemotherapy backbone such as fludarabine and cyclophosphamide? So I would have to conclude that in this setting, although I think the data is exciting, I’m not sure that that’s a good rationale for rushing out to use chlorambucil with obinutuzumab.

KR: Or bendamustine and rituximab, if you say fludarabine and cyclophosphamide.

SOB: Or, that would be reasonable, would it be better than bendamustine and rituximab?

MH: So BG to stay fancy actually, the BGs of the…

KR: No, but I partly agree with Anders because it gives us an opportunity to talk about the big pharma, the pharmaceutical industry’s responsibility for discovering and demonstrating special efficacy of a new drug, that when they come to the point of pricing it they ought to think of not merely the profit for their stockholders but also of the population and not to make it so prohibitively expensive that it becomes impossible for a socially conscious doctor to, in good conscience, use that drug. As we have seen, an enormous uproad in CML studies with the pricing of the new kinase inhibitors, that is not an isolated CML study, it should be considered and kept in mind by the pharma in pricing newer drugs.

MH: That’s a very, very good remark and in particular since you are getting, not only one but certainly one, two, three, four, five of these drugs over the next two years.

SOB: Absolutely.

MH: That is a good start for the other exciting topic of the meeting, the new drugs besides GA101, the kinase inhibitors, the Bcl-2 inhibitor. Maybe Jan Burger can give a little overview of what we have seen so far on these really exciting novel agents, they are now in the clinics and they are all thrilling us because we are going into a new era of CLL treatment.

JB: Yes, the most advanced one is certainly the BTK inhibitor ibrutinib and the PI3 kinase delta inhibitor GS-1101 from Gilead. Both are moving quickly forward in CLL and in other B-cell malignancies. The most responsive patients seem to be CLL and mantle cell lymphoma patients where we’re expecting approval of these drugs in the near future. They target different enzymes, BTK on the one hand and PI3 kinase, but they’re associated with a specific signalling pathway and some of the excitement is related to now having something targeted where we target a signalling pathway that we feel is important for the biology of the disease. So that’s one interesting aspect of these kinase inhibitors and then the clinical pattern of responses where lymph nodes quickly shrink; patients who have B symptoms, those B symptoms resolve quickly, they are not immunosuppressive or myelosuppressive, haemoglobin levels improve, platelet levels improve. All this combination of all these effects make this whole class of new agents very attractive for patients and certainly also for the physicians. So what has been discussed mostly, based on the excitement about the recent New England Journal paper about ibrutinib in mantle cell lymphoma and in CLL, this agent has been at the forefront of discussions here at the meeting and the data have been presented. We have high response rates but these response rates initially are characterised by lymphocytosis so the redistribution of the cells initially when you give a single agent kinase inhibitor is an issue which precludes some patients to achieve remissions. Combinations have been discussed and side effect profiles have been discussed. Then the issue still remains of long-term efficacy; we have median progression free survival on these trials in the range of 70-80% at two years, so that’s encouraging and that’s generating this excitement.

MH: Now Stephan Stilgenbauer yesterday showed exciting data as well, not challenging but actually working on the concept of the mechanism of action where he showed that a number of patients become resistant and all of a sudden they have real mutations in the binding domains or in a downstream target, PLC-gamma. So the pathway all of a sudden gets resistance mutations pointing to the fact that these pathways driven by the B-cell receptor are actually a real target and not the micro-environmental cells.  It’s the tumour cell itself that is targeted, at least in some of these patients. Now, you are an expert on the micro-environment and I scratch my head all the time about these data, what do you make out of all of this because you had data also showing that this is not the only effect, some of the effects are mediated by cell-cell communication, micro-environmental clues, chemokines and not directly mediated eventually through the BTK inhibition in the tumour cells? So is there a conclusion?

JB: Yes, I think those data he was presenting are exciting. He was showing mutations in BTK in five out of ten patients who become resistant. Overall this is still a very small population of all patients being treated so it’s not a common event; in treatment we have hundreds of patients on ibrutinib now over several years. So it’s a rare finding and it’s interesting to see in about 50% that we have BTK mutations. It speaks to the fact that this is a non-redundant pathway if BTK is mutated in people then you get this immune deficiency, XLA. So it speaks to this being a really important pathway for B-cells. If you inhibit that for a long time in patients you certainly worry what’s going to happen to the normal immune system of patients, that’s another unanswered question. It is good to see that immunoglobin levels don’t seem to come down and patients usually don’t seem to have increased frequency of infections but it still remains early and that’s certainly something we have to watch out for in the years to come as we develop these agents.

MH: Now Professor Rai, you have seen so many things coming and going over a long time in CLL history and now this is all new. With a little bit more distance you could say, ‘Well, I have seen so many things and they all disappear,’ or do you think this is a real innovation in the field, all these novel agents?

KR: I’m very excited, as you point out, that over the decades I have seen a fair number of new drugs come in with excitement. But these new drugs are completely different and I think that even if they do not pan out over a long-term follow-up to be as exciting as they are in 2013 I can predict, and I bet, that they will remain important contributors to an improved, significantly improved, level of treatment of CLL in the future. And maybe, and it is not an unduly optimistic view, maybe we will convert CLL into a chronic disease as imatinib and company have done for CML.

MH: And that may change the practice of the high risk patient population in particular, as we said earlier, and the standard treatment for some of these patients, in particular p53 mutated or deletion 17p, is allogeneic transplantation and one of the things that we should address in this educational spot is basically how are we going to proceed with allogeneic transplant in this time? I can say from my own practice I have patients that are very well informed and they say, ‘I would rather like to wait until they come into the pleasure to get these novel agents,’ so they postpone the transplant as long as they can. This morning John Byrd was saying in his centre, it’s also a transplant centre like ours, he’s seeing strongly decreased numbers of patients going into transplant. So what’s your experience?

MH: And how about the MD Anderson, is that the same happening over there?

SOB: I think that it’s obviously very difficult for a patient who is taking an oral drug that hardly has any side effects and is having a nice response to then make a decision to go for a dramatically alternative approach to therapy such as a transplant. Historically, as you alluded to, we’ve always tried to get the patients with 17p deletion to a transplant because they have very suboptimal responses and if they progress and relapse they don’t do well. I would agree that when I discuss this with the patients who have been on ibrutinib more likely than not they would prefer to hold off. Does that have a downside to it? Well it does because we’ve seen patients, now remember everybody in the relapsed refractory trial that got ibrutinib had failed every other therapy so it’s not like now if they relapse off of ibrutinib you have a lot of options for them. So we have had some difficulties in some patients with actually being able to get them to a transplant if we waited for them to relapse. Obviously if, going forward, the drugs are moved up in terms of the refractoriness of the patient such that one might have alternative strategies to salvage a response, then I think everybody would be more comfortable delaying the transplant. In the group that have made up all of the constituents of these trials right now it’s still a very difficult decision because these people are so refractory going into the trial that realistically do we have an opportunity to get them back into remission once they do progress? I can say from personal experience not always. But again as we start to use these drugs in a different way, bring them up into a perhaps less refractory population, then for sure the transplant will get pushed back without question.

MH: And in addition to these kinase inhibitors we may have another principle, as was said by the transplanters themselves actually this morning, and that’s the genetically designed T-cells, so while you introduce which was a probably non-toxic transplant principle in a way which is eventually then getting rid of all the transplants. Would you agree with this notion? If you see patients are they talking about not wanting an allogeneic transplant any more after these developments?

AO: We also have a number of patients on ibrutinib right now, 17p minus, who are eligible for transplant and we have this as an on-going discussion with the patients all the time. At the moment we keep our fingers crossed and keep them on the drug but our strategy at the moment is to watch out for very, very early signs of relapse and then switch immediately. I don’t know if that is right but what I think is important is to get a consensus that we are willing to change when we get new information so people have something to follow, some strong guidelines in this situation.

MH: One thing, I think we reach a consensus very easily but it’s important in educational missions and spots like this one to state that autologous transplantation, in particular in the era of these novel agents and developments, has no place in CLL anymore. We have not done any autologous transplant in CLL for at least five years now. I think that’s fair to say. I think we may summarise this and maybe by doing a short summary each individually about his or her personal highlight of this meeting. I will start because it’s a very personal history. This morning, actually, the co-worker of my group, Dr Fischer, was presenting data on the long-term outcomes, we discussed that before, and I was asking her last week to do a couple of calculations and I didn’t see the data so I discovered them this morning while she was presenting them. I found it particularly interesting that with combinations of cytogenetics and unmutated CLL patients you can have very, very long-lasting remissions without any progression over many years. That is again challenging the concept because I was coming to the meeting saying, ‘Well everything will be pushed away by the novel drugs,’ and all of a sudden we have really two competing concepts, one that is potentially I shouldn’t say curative but really getting very, very long remissions in the low risk patients. I found it very beautiful that she was coming in with new data that I was totally thrilled about. What’s your personal highlight on this?

AO: I think it’s that we are on our way towards personalised medicine; we are understanding better and better who should receive FCR in the beginning, who would have very long lasting remissions based on that. We are about to understand better who need the small molecules quite early. But if I should highlight some individual things, the phase I data on the Bcl-2 inhibitor also showing promising effects in 17p minus patients, that is very interesting. So it’s very good that we have several new small molecules targeting different pathways since mutations are something that we will see with different pathways so we always need another pathway and another drug to target it.

MH: Susan, how about you? Your personal highlight?

SOB: Actually I would have to say that mine was the same as yours and, as you know, Kirsten presented the long-term follow-up of the FCR[8] trial so we saw this plateau on the curve and then Bill Wierda presented the data from MD Anderson and they were remarkably similar, both suggesting that we can identify a good risk population who are in remission ten years after therapy. Then what’s exciting about that is for the first time you actually heard people saying the word cure; nobody was saying, ‘These patients are cured,’ because I don’t think people will leap to that but saying, well, could they be or might they be? It might be very interesting to go back on these patients, both yours and ours, and when they come back in next time do MRD assays. I actually have done that in a few of my patients that have been in long-term remission for ten years and some of them are still MRD negative. So, again, could they relapse at fifteen or twenty years? Maybe but if you can get chemo for six months and get a remission for twenty years I don’t think anybody’s going to argue about that. That’s why, again, I’m very excited about the new drugs, I’ve been very involved with their development, right from the beginning but I’m a little bit cautious about saying we’re going to go strictly to using new targeted therapies with no chemo now that we see these kind of outcomes. I think we can identify that population, it’s not that we’re not sure who they are, we can identify them.

MH: Jan Burger.

JB: Yes, I would say what the meeting is highlighting from my interest and perspective is that CLL has really become a model disease for studying disease biology and translating basic research findings into novel therapies. So over the last years the theme of cell-cell interaction, signalling pathways, the microenvironment has emerged and has become a major topic here at the meeting. It’s great to now see that we better understand how the novel therapies are working, we know it’s based on assays where cells talk to each other, and seeing that a lot of different groups presenting that in posters or presentations is exciting. I’m not aware of any other cancer where we are making so much progress in such a short time.

MH: Kanti Rai, the last word on this?

KR: Well, far from being the last word but I share the excitement that we all have noticed in treatment of CLL in this particular iwCLL. But I am more conservative, I do not jump with joy. I feel that there is objective evidence of major progress but, as has been pointed out, we have to be cautious because these are new, promising drugs with initial results extremely exciting but more excitement is that other drugs also on the targeted basis are being developed. As far as I know there are a couple of other drugs on PI3 kinase inhibition with a larger target than the current one that we are using in clinical trials, other drugs affecting BTK. Similarly a number of other drugs which are currently in early trials, we never had that kind of time in CLL treatment before and I think that we have to give ourselves approximately three to five years from today before we can start to talk about cure, long-term remission, changing the natural history of this disease which, until now, we have failed to achieve.

MH: That’s a good final word and I would not add anything to this except to say one of the wonderful things happening here is a confirmation of the uniqueness of the iwCLL because it’s really a unique group in the field of haematology, or maybe in all cancers, of people meeting in a friendly atmosphere. And if I had to add one more reason why CLL is making such fast progress right now it’s also because many scientists in the world that are organised or come to these iwCLL meetings, for many years sometimes, are co-operating, changing ideas, respect each other and the entire meeting is actually carried by this atmosphere as any other previous meeting in this collegiate atmosphere is a key event, a key factor if we make such a rapid progress. With this we can conclude and wish the audience a nice afternoon or evening, whenever you see us.