ASH 2015

ASH 2015: Latest in CLL

Prof John Gribben - Queen Mary University of London and Barts Cancer Institute, London, UK
Prof Stephan Stilgenbauer - University of Ulm, Ulm, Germany
Dr Alessandra Tedeschi - Azienda Ospedaliera Niguarda Cà Granda Milano, Milano, Italy
Dr Patrick Thornton - Royal College of Surgeons, Dublin, Ireland

JG: Welcome to Orlando. We’re at the 2015 ASH meeting. I’m joined here by my colleagues, I’m John Gribben from London; Alessandra Tedeschi from Italy, Patrick Thornton from Ireland and Professor Stephan Stilgenbaure who is omnipresent at this meeting from Ulm. We’re here to talk about lots of the exciting things again which we’re seeing in CLL and yet again we’ve seen lots of new data, particularly on the novel agents which is what I’d like to focus on today. So, Alessandra, you had the opportunity to present… well, the big breaking news at the meeting was the RESONATE-2 study. This, of course, is the study which is the up-front study of ibrutinib. So do you want to tell us about what the findings are of the study and what you think that means for our CLL patients?

AT: The importance of the study was that it’s the first randomised study involving ibrutinib in first line treatment in treatment naïve patients and it was addressed specifically to elderly patients. It was a comparison between ibrutinib and the standard treatment that was considered at the time the study was designed, the standard treatment chlorambucil.

JG: A lot of these studies have come in for criticism that the comparative arm is never really the standard of care that we have right now. What do you think about chlorambucil nowadays as a comparative arm for a study?

AT: In this moment chlorambucil is not the standard of care for elderly patients but at the moment the study was designed was considered the standard of care. So, of course, now the comparator would be chlorambucil plus obinutuzumab but in those days was just chlorambucil. But apart from the control arm, I would say that ibrutinib showed to be highly effective.

JG: Spectacular is the word I would use to describe the results here.

AT: Spectacular, yes. Great progression free survival, a significantly longer overall survival, even though there was the possibility to cross over for the patients when they had progressive disease. So the overall survival curves are dividing and this is an important issue.

JG: This has been a recurrent theme of all of these studies of the novel agents, that even with a crossover design we still see overall survival differences at the end of the studies suggesting that it’s not the right approach to start gently and keep these drugs until later. Is that how you interpret that data too?

AT: Yes, of course.  And I think that this is a bigger problem with elderly patients because if you don’t give immediately a treatment that may control the disease, what happens in the elderly with comorbidity, they worsen their condition and then they are not clinically fit to receive a second line treatment. I think that this important most with the elderly because of their comorbidities so the outcome is worse in these patients.

JG: Sure.

SS: Sorry to interrupt here, John, but I think this is indeed a point worth noting that we have started seeing this with the introduction of biological agents actually now, dating back you could almost say to CLL8, with the CR versus FC where for the first time we saw this overall survival difference. And not stipulated in the trial but available was a crossover because the patients could have been treated with rituximab containing regimens in relapse. Still we saw that and it is really like with biological agents that we started to begin to see this difference.

JG: I think one of the features, of course, is how the IWCLL criteria define progression. To progress above base line is not how we would retreat a patient at relapse. So I do think the barrier is set sometimes too high. We would not wait until a patient had progressed, the way an independent review panel does, before perhaps we might do treatment. But that notwithstanding, the results are absolutely clear-cut, they could not be more clear. Do you think now that we are sitting all here from Europe, do you think you really believe that ibrutinib will become the established front line therapy for elderly patients in CLL?

AT: I think that there will be some patients that can benefit from ibrutinib for sure, maybe the more frail patients. Still in the fit patients immunochemotherapy has a role in this moment. Of course not the very frail patients but there is a part of the patients that can benefit from ibrutinib.

JG: In fact, the randomised trials suggest that over-65 patients should have a survival advantage for having this therapy. So, Patrick, do you think that in Ireland it will become a regular therapy for front-line patients on the basis of this study?

PT: Well I think for patients with p53 deletion there should be no question about it, it should be first line treatment. When you look at overall ASH this year for CLL there’s an overwhelming amount of information on new studies, new antibodies, novel agents and it’s hard to see any report which doesn’t say overall response rate greater than 80%. We have a new antibody with obinutuzumab and it’s improved the efficacy of chlorambucil. The question always is you always have to have your drug reimbursed outside of clinical trial so sometimes it can be an uphill struggle, even though you’ve got extremely effective drugs to convince your authorities that these drugs are worth paying for.

JG: By every standard that the authorities would ask for, a randomised trial against an appropriate comparator showing an overall survival, that should be enough to… this should be paradigm shifting.

PT: This should.

JG: That has always been the standard in which we’ve changed therapy before. Is that not the case now here too?

PT: It should be.

JG: Yes. Do you think in Germany that front line therapy will move?

SS: I think so. I think it’s just great to see that we have all these options available now, we shouldn’t argue that now we don’t know what to do. It’s great that we have these options for our patients and even as we stated that there was this overall survival benefit we should say, well, for some patients maybe obinutuzumab plus chlorambucil would be an option. It’s a finite treatment duration, you can probably get into a remission in the majority of patients with this regimen and then you still have ibrutinib also to salvage them. Because this was actually not analysed in the trial, if this strategy in the longer run could not, at least for some patients, also result in very, very beneficial survival times.

JG: Sure. Well, of course we’ve already completed accrual of the iLLUMINATE trial which will give us the answer. Maybe even as early as next ASH we may be seeing a late breaking abstract from iLLUMINATE. So, Patrick, other than RESONATE-2, what has been the highlight of this meeting from your perspective?

PT: Well, I think it’s hard to pick out, there’s so much information. For a while now we’ve had our novel B-cell receptor antagonists with our idelalisib and our ibrutinib. We’re getting more and more data coming through and we’re having presentations on combinations of these drugs which is very interesting. We have the new obinutuzumab, and Stephan presented the subset from the CLL with the bendamustine and obinutuzumab which maybe we’ll have time to chat about after that. Another thing which is certainly worth mentioning and unescapable is the BH3 mimetic, the venetoclax, the Bcl-2 inhibitor. It was very striking the presentations, the very deep remissions, the complete remissions and even people who remain in remission when the drug was stopped. I just think it’s a very exciting drug, I’m looking forward to participating in clinical trials with that.

JG: Sure. So, Stephan, I almost don’t know where to start with you, you’ve presented so much at this meeting. There’s lots of things we could pick up on, and particularly you’ve been presenting a lot of new data. So, of course, on the theme of venetoclax you’re presenting the data of the phase II 17p trial. So what are the highlights of that?

SS: I think venetoclax is really a new treatment paradigm in the sense that now we have first ever, actually, an agent available that is really efficiently targeting Bcl-2 and Bcl-2 is almost a unifying feature of all cancers. It is very highly expressed in many cancers, in particular in CLL, and therefore it’s biologically a very valid target. This trial, together with other data, shows that this can really be tackled in a clinically meaningful way. Nevertheless, it needs to be handled with care because the efficacy is so great and so rapid in onset that you have to use a careful ramp-up dosing scheme and have to monitor the patients not to have too much of a good thing.

JG: Now, lots of pre-clinical data we saw at this meeting also, looking at the potential mechanisms of synergy of these types of agents. Of course, we can look at ways in which we can put together all of the agents we’ve been talking about here but an obvious combination would be ibrutinib venetoclax combinations and I think lots of those sorts of trials going to start. So if we think that ibrutinib is an expensive agent and we can only presume that venetoclax is going to be an expensive agent, what do you think it’s going to take for us to be able to offer doublets or triplets of these agents together to our patients?

AT: We are going to have the same scenario for multiple myeloma in chronic lymphocytic leukaemia. What I think is that there must be well-addressed studies to understanding which categories and which categories of patients may benefit from certain types of combinations.

JG: It’s a good analogy to use, to be thinking about CLL compared to multiple myeloma. Do you think, Patrick, our goal should be that we just prolong survival by sequencing the drugs or do you think we’re on the cusp of potentially going all the way for very deep remissions and they’re when you start to use the cure word in CLL with the powerful agents that we now have available that we’ve heard about at this meeting?

PT: Theoretically, if you can get a deep enough MRD negativity then by the time that person has a meaningful relapse they may have outlived their life expectancy anyway so effectively it’s a cure. So, once again, if you get very deep remissions and minimise the clone to very low levels then perhaps you reduce the possibility of more regressive clones coming through and less likelihood of escaping treatment further on. So I don’t know the best way to time these drugs in combination but certainly I think in all cancer combinations of drugs seem to reduce resistance and treatment escape so I think it certainly makes sense that these combinations should be explored.

JG: Until now we’d entered the era of chemo-immunotherapy. Do you believe that there’s a role for antibodies in combination with these agents or do you think they should be used alone?

PT: I think there’s some suggestion there’s some synergy with the BH3 mimetics and anti-CD20 antibodies. The other, idelalisib seems to be always combined with rituximab so it is likely that the anti-CD20 antibodies will continue, I believe, in treatment regimens. I think the obvious question is which anti-CD20 antibody we use. Looking at the data it seems to be almost very difficult to get that extra 2-3%, it seems logical that obinutuzumab is your best antibody. Stephan’s data with the GREEN study, certainly the CRs and the blood and the bone marrow are certainly more impressive than you see with rituximab. So I would imagine that that would probably be the antibody of choice going forward in combination with these drugs.

JG: So we’re on to the GREEN study. Now it’s very unlike a Genentech Roche study to have a thousand patient study that doesn’t really have a straightforward comparator. It’s a very unusual design of a study from this company. What are your conclusions of what we learned from GREEN?

SS: Right, I think John, as you say, there has been a debate if GREEN, almost a thousand patient study, is a meaningful thing without having a randomised comparator. However, I think you can look at it in another way. Actually, as you know, in GREEN we enrol front line patients and relapsed refractory, we enrol fit and unfit, and then several risk mitigation schemes with regard to infusion related reactions are applied. So in my opinion actually from all these variations you could say that actually GREEN is a series of ten smaller phase II studies combined into one concept. Since everything is standardised in that trial, up to even MRD assessment centrally, I think this makes perfect sense not to have a fragmented small set of some smaller phase II studies but combine it into one big concept. As we discussed, trial design is challenging today with these results that we have so we have to tackle that with new concepts such as GREEN I think.

JG: Now on that issue we’ve been hearing the whole meeting, and you raised the issue, Patrick, about response rates being never less than 80%. Have we set a bar so high now that it’s going to be more and more difficult to bring in other new improvements? And if we look at saying that we want to bring in doublets for front line therapy how do we beat the new standards which are looking like a pretty flat line along the top from what you showed, Alessandra?

AT: It’s hard to understand with these drugs which is the real meaning at the end of complete remission. If you look at the data of the RESONATE study we had only 11% of complete remission and the progression free survival curve and the overall survival curve are quite perfect, I’d say. So we need longer follow-up to understand what is going to happen in these patients. We had 11% complete remission and a very prolonged progression free survival. So I don’t know if the monoclonal antibodies will have a lot in [?? 15:52].

JG: So you think it won’t necessarily be the overall response rate but the complete response rates and the MRD rates that are going to drive us going forward. Of course, at the moment still the regulatory authorities haven’t quite accepted those as valid endpoints for the study but we’re very hopeful that will change going forward. Stephan, you are also, of course, presenting data looking at identification of factors which are risk factors for progression. Now that raises the issue, Patrick already talked about the idea that maybe the front line for 17p, but do you think we might get to an era where you look at the risk stratification and you have different types of approaches for different patients based upon the risk? Is that maybe something that happens going forward?

SS: Sure, I think this is where the field evolves to isn’t it? We have already in routine practice 17p deletion and TP53 mutation which clearly should guide therapy for every single patient in the front line setting and in relapse. Now new adverse events are arising, for instance there are patients who you, despite their great results, would not like to put on ibrutinib who had a history of bleeding, who have anticoagulation that is urgently required, who had maybe a history of severe arrhythmias. So probably in our trial design we will also refocus not only on molecular factors but also on clinical characteristics of the patient that make the one patient more suitable for the one option or for the other option. So I think we have to be a bit innovative here to go away from the old all front line patients are the same.

JG: Now, the other role that novel agents could have, of course, is in combination with chemotherapy. We’ve been talking so far about novel novel combinations; so we’re seeing the data here of idelalisib in combination with bendamustine rituximab showing an improvement in outcome there. Of course we’d already seen the HELIOS study of bendamustine plus ibrutinib being superior. My own view was that I could see very clearly what the ibrutinib or idelalisib is adding to the bendamustine but I’m not quite sure that I’m yet seeing what the bendamustine is adding to the ibrutinib or the idelalisib. Do you think going forwards, that apart from the younger, fitter patients for whom FCR remains the standard, that chemotherapy is over? Or do you think that we’re going to be developing these drugs in combination? Patrick, what do you think?

PT: I am inclined to agree with you, certainly with the HELIOS study where we didn’t see what the bendamustine was adding at all. With the idelalisib bendamustine rituximab it’s certainly very impressive results. The question always is with chemotherapy that CLL is a disease of the old in general and, relating back to what you said earlier, when you have such very good overall response rates people will start to look a little more at toxicities and I wonder how much chemo adds to the toxicity and the efficacy. I think for going forward, personally, my own view is that we’re probably going to be moving away from chemotherapy. There are, as a tangent to that, some people say that some chemotherapy may increase the efficacy of antibody kill and maybe that needs exploring more but overall we should be at least considering chemo free treatment for CLL.

JG: What do you think, do you think the era of chemotherapy is over?

AT: I don’t think so. I think that data on FCR treatment are very strong in this moment and we have still to use FCR in fit patients in first line treatment.

JG: On that concept, of course, a lot of my patients all object to the fact that all of these studies are open to elderly, less fit patients and they feel that they’re not getting the opportunity to…

AT: They’re abandoned.

JG: They’ve been a little bit abandoned by the field and a bit left behind. I used to have to try to make everyone’s CIRS score less than six to get them FCR, now you have to make it higher than six to give them a novel agent. I know that there are ongoing trials of novel agents versus FCR but, Stephan, what’s the German CLL Study Group’s view of the young, fit patient and the novel agent versus the FCR or BR standard?

SS: Sure, it may look to you like the young, fit patients are the ones that have the least good treatment options. Obinutuzumab, possibly the best antibody in CLL, is not licensed for them, let alone ibrutinib, idelalisib or venetoclax, at least in the front line setting. So this may look a bit awkward. On the other hand we have to say, as Alessandra said, we have really FCR in some populations achieving with manageable toxicity really years and years, maybe even a decade, of remission, treatment free time, the patient is off drug. We know that with the new agents, they’re only pills, nevertheless a little bit of arthralgia, maybe headache, maybe bruising. In the longer run this can be quite bothersome so there are still risk benefits to weigh and I’m certainly well known as a friend of a chemotherapy free future, however, in the present a chemotherapy free world is not already arrived.

PT: I agree if you’ve got a mutation IGVH and a 13q deletion and you have FCR you will have age-matched controls to people who don’t have CLL. That certainly is extremely difficult to argue with but are those patients the majority of the CLL patients that you see in your clinic? Fit enough for FCR and mutation IGVH and a 13q deletion?

JG: Absolutely.

PT: It’s not the [?? 22:17].

JG: One or two word answers for this question but do you think particularly if we start using ibrutinib front line that we may change the natural history, prevent the emergence of these resistant clones that emerge? Do you think we could change the way in which we start to see 17p evolve in relapse?

AT: I don’t think so. This cell is a very intelligent cell so maybe…

JG: So we have to hit it from different directions, so again we come back to thinking about doublets.

AT: Yes.

JG: But you’ve got to see what this meeting has confirmed is what we already knew, that these novel agents have completely revolutionised the way we think about and are able to treat this disease. So there you have it from ASH in 2015 – for CLL great news all round in terms of the continued studies we see of the promise of the B-cell receptor inhibitors, their efficacy in CLL and new opening up from the RESONATE-2 trial demonstrating for the first time the efficacy of this agent up front, hopefully leading to a licensing of this agent. A new era opening up for CLL patients.