EHA 2016
The latest in CLL from EHA 2016
Prof Peter Hillmen – Leeds Teaching Hospitals NHS Trust, Leeds, UK
Prof Paolo Ghia – Università Vita-Salute San Raffaele, Milan, Italy
Dr Chris Fox – Nottingham University Hospitals NHS Trust, UK
Dr Constantine Tam – Peter MacCallum Cancer Centre, Melbourne, Australia
PH: Hello, welcome to 2016 EHA. We’re with ecancer.tv and we’re going to discuss the developments in CLL discussed at the meeting here in Copenhagen. I am joined by three friends and colleagues working in CLL - Con Tam from Australia, Chris Fox from Nottingham in the UK and Paolo Ghia from Milan. So we’ve had a lot of interesting data that’s been presented at the meeting and I’d like to first ask Con we’ve seen presented some data with ibrutinib in poor risk disease, would you like to summarise your thoughts about that data?
CT: Sure. So Dr Jones presented an aggregate analysis of 243 patients with 17p deletion CLL that were treated across three ibrutinib studies. So the aim was to group all these patients together and analyse the aggregate outcome of ibrutinib in relapsed 17p disease. The major messages to come out were that the response rates were remarkably consistent between the three studies, so about an 85-90% response rate. The complete remission rate is still low at about 6-8% and that the progression free survival when you add the three studies together has not been reached at 30 months and is projected to be roughly about three years. But there is a continuing fall in the PFS curve with no plateau on that curve so the patients are continuing to relapse. To put this in context, these are still the best results that we’ve seen in 17p CLL, definitely much better than anything else we had in the age of before ibrutinib. When analysing the risk factors for poor outcome the risk factors came out as being a high LDH, bulky disease, having many lines of therapy, but in fact the most important risk factor turned out to be a complex karyotype and patients with 17p and a complex karyotype did very poorly. In this day and age where we’ve started to ask what is the role of allogeneic transplant or additional therapy in patients treated with ibrutinib, the group that we really need to focus on are the ones who have got a complex karyotype.
PH: We also presented some data, that was in 243 patients I think, but we also saw some data from the real world with almost 3,000 patients treated in an access scheme and the data looked very similar so it does seem that across the board the ibrutinib treatment the responses we’re seeing in the trials is being maintained. Chris, we’ve also started to look at when we should use this drug and there was an interesting abstract which you were involved with in terms of lines of therapy.
CF: That’s right. This was a large analysis of both the RESONATE study for relapsed CLL and the RESONATE-2 study for first line. That allowed quite a large data set with mature follow up looking at the PFS by line of therapy, so first line, second line, third line and so on. The striking thing that came out of that data set was that if you used ibrutinib further than second line then although ibrutinib was still very effective and we had durable responses, the PFS did drop off quite significantly. So if it was used as third line then it was down from the 80s, 90s, down into the 60% for PFS, 69%. So that gives us some sense that although this drug is effective even in advanced stage disease perhaps we should be using it more wisely earlier on in therapy and that will inform the design of some of the future studies I think.
PH: So perhaps the treatment with chemotherapy clearly alters the behaviour of the disease to even targeted treatments such as ibrutinib. I guess how you presented data on the RESONATE-2 trial, the front line comparison of ibrutinib with chlorambucil and of the quality of life and those sorts of issues in that trial.
PG: Yes indeed, the RESONATE-2 study has been already published in December and presented at ASH and it is the study based on which the EMA very recently approved the use of ibrutinib in all CLL patients, regardless of the line of therapy. Indeed RESONATE-2 is a study focussed on patients elderly and/or with comorbidities and the use of ibrutinib was compared to chlorambucil that at that time, the time of design of the study, was still the standard of care. We know the results, we know that patients responded better with ibrutinib, they had a longer PFS survival and a longer overall survival. So in this study at EHA we also updated the quality… we also showed that there was an improvement in quality of life and wellbeing of the patients and, of course, this correlates also with the efficacy of the drug because the patients improved hematologic function so of course the fatigue due to anaemia disappeared when also the anaemia recovered. Also symptoms disappeared more quickly so that was one of the main reasons also to have an improvement in quality of life and wellbeing, again suggesting that when using a better therapy patients feel better also because the disease is responding better.
PH: So generally the ibrutinib as a single agent seems to be well tolerated in most patients but we do have some patients where we struggle to give the drug to them for cardiac reasons or other issues. You’ve touched on the design of RESONATE-2 in that that was against the then standard of therapy for CLL but of course this field is moving so quickly now and we’ve seen data at the meeting in terms of the next generation of chemo-immunotherapies for elderly patients, so chlorambucil plus obinutuzumab, and we had an update from the German 11 trial here.
CT: That’s right, the Germans presented an update on their CLL-11 study comparing chlorambucil versus chlorambucil plus rituximab versus chlorambucil plus GA101. This is data that was focussed on the proportion of patients who reached MRD negativity which is not something that we would normally consider in a study for elderly patients. But nevertheless it was very clear that patients who got the obinutuzumab arm had much deeper MRD than the rituximab arm and the MRD is basically not achievable with chlorambucil by itself. The interesting thing is that when they looked at the outcomes of patients, their progression free survival by their MRD status versus whether they got rituximab or obinutuzumab or not, it was just like the German CLL-8 study, the MRD is what matters. So if you’re MRD negative you do just as well regardless of whether you got rituximab or GA101, if you’re MRD positive you do just as badly regardless of which arm you got. The difference between the GA101 and rituximab is that obinutuzumab is much more likely to get people into MRD negativity. So that resets our mind-set about patients, elderly patients. It shows that MRD is a relevant endpoint and in particular it means that they can give a limited duration of therapy, get into remission and do not require ongoing therapy like you do with, for example, ibrutinib.
PH: There are challenges, though, with MRD in any setting but a lot of the MRD is peripheral blood MRD, the follow up of the trial is relatively short and if you’re thinking about prolonged remissions you’re really, in CLL, talking about many years, not a follow up of two, three, four years.
PG: That’s a point. Maybe I’ll make two points, the first point is that indeed the study as described showed that indeed achieving MRD is the key point, regardless of the kind of therapy that you are using. But also what is interesting that maybe we don’t need to use the maximum therapy in all patients to achieve MRD so this again points to the fact that we have to learn to tailor the therapy to our patients, probably based on a better knowledge of the biology of the disease of each single patient. So in some patients maybe we need to use chlorambucil plus GA101, in some others it will be enough using rituximab. Regarding MRD, there was also another interesting study, the update of the study, the randomised study, comparing bendamustine plus rituximab versus ibrutinib plus bendamustine plus rituximab. The update from ASH shows very interestingly that the progression free survival keeps on improving with the association of ibrutinib plus immuno-chemotherapy and the quality of responses improve. Now almost one-third of patients reach complete remission and almost 20% of patients, 18%, reach MRD negativity. The interesting point here, of course because ibrutinib is given continuously after stopping bendamustine plus rituximab, is that reaching MRD negativity in that arm is not really relevant for progression free survival because patients indeed continue to receive a maintenance therapy.
PH: But in that trial the combination between ibrutinib with BR, of course it’s in the first six months, and we’re seeing the MRD emerging later on so it almost is like we’re resetting the disease, we’re debulking the disease with chemotherapy and then the ibrutinib probably has an effect later on in terms of eradicating detectable disease. That may suggest it’s just a time thing rather than a synergy. Because we’re not seeing really MRD responses with the novel agents or with certainly the B-cell receptor inhibitors.
CF: No, and it’s difficult really to make a clear judgement about that yet. We know MRD is extremely important and a great surrogate for PFS and yet with the BCR antagonists we’re not seeing that. So what is the best parameter in that setting? By the iwCLL criteria the CR rate does improve with time with ibrutinib but, you’re quite right, we’re not getting to MRD negativity. So comparing them across trials might be quite difficult actually.
PH: We have the next generation, if you like, of B-cell receptor inhibitors, acalabrutinib, we heard about it for the first time at ASH last year and now we’ve had the cohort of treatment naïve patients which looks interesting.
CT: Yes, so 74 patients treated on the initial phase I/II study of acalabrutinib and the messages that came out were essentially that there were very high response rates, 97%, but nobody reached a complete remission. So once again MRD eradication seems unlikely within the second generation drug. There appears to be a better tolerance of the therapy with a reduced incidence of… there was no atrial fibrillation, no major bleeding, a fairly low rate of spontaneous low grade bleeding. Somewhat intriguing, BTK occupancy in that it requires a twice a day dose to sustain for BTK occupancy whereas ibrutinib could do it on once a day, so somewhat intriguing. But nevertheless it looks like a favourable toxicity profile.
PH: So Chris, the follow up for acalabrutinib is relatively short so we have trials ongoing now. So where are we placing this drug, how do we show where it fits in the treatment of CLL?
CF: As you know, Pete, there’s a large study ongoing, a randomised phase III, the ACL-006 study which is a head-to-head of acalabrutinib versus ibrutinib for patients who have had at least one line of therapy but have a p53 or ATM deletion of at least 7%. So I think that’s a really interesting study and in some ways it’s quite bold. The toxicity profile looks very favourable but I think it’s probably too soon to say where we’re at in terms of which is the optimal BTK inhibitor.
PH: We have a front line trial as well so the field is moving very rapidly in terms of responses to these drugs. But one of the issues is continuous therapy and we’ve heard some data at this meeting regarding venetoclax and ABT199 and we’re now getting to the stage where patients are stopping treatment. We saw some data from Australia, actually, Con.
CT: Yes, we contributed but it was really from the two international studies with venetoclax by itself and venetoclax plus rituximab. The major message to come out is that if you add rituximab to venetoclax you do improve your complete remission rates to the order of about 50% and that is confirmed on a multivariant analysis confirming that rituximab was useful in improving that. The second message to come out is that patients who become MRD negative on venetoclax can actually come off therapy so there has been a total of eleven patients who have come off therapy now and two patients came off therapy with detectable MRD and they relapsed two years later and they were retreated and regained control. The remaining patients came off therapy while they were MRD negative and with a shorter follow up none of them have relapsed so far. So it looks as if you can get probably at least two years of [?? 14:10] remission from venetoclax even in the relapsed refractory setting.
PH: And there have been a couple of patients where when they’ve relapsed it’s been restarted and patients have come back under control which is really important with these trials, that in real life patients are coming off treatment and we need to know how we treat them afterwards because the very early reports were that patients relapsed very quickly and were difficult to control but in these less heavily pre-treated patients we probably can rescue them. In terms of relapsed disease, so we’ve had a lot of data and still compared to BR or the conventional therapies the small molecules have a better outcome.
PG: Yes, definitely. It is interesting because now we are facing a strange situation, we have a lot of novel molecules. We have some molecules on one side that have to be taken continuously. I don’t think that in this moment we can envision this continuation of therapy with the BTK or the PI3 kinase delta inhibitor because they don’t really reach CRs or at least MRD negativity. But still the progression free survival of ibrutinib, for example, like acalabrutinib, look very, very promising and definitely seem even better as compared to other regimens like chlorambucil associated even with obinutuzumab where indeed you can reach MRD negativity but the progression curve of all patients are a little bit shorter. So we are really facing a dilemma in treating our patients because we have really to understand what the best therapy can be for each of our patients. So probably we need to go back to school somehow and learn more about prognostic markers or predictive markers in each of our patients.
PH: And the combinations are the other thing which are emerging now. So we’ve had data for bendamustine plus ibrutinib, bendamustine rituximab plus idelalisib. Do you think that’s the next step forward or what are the exciting developments in terms of combination therapies?
CT: I think combination of biologicals are the way to go. So there are now multiple studies of, for example, ibrutinib plus venetoclax which are either about to start or are recruiting, including your own in CLL. Then there’s also a UK study of ibrutinib venetoclax and GA101 in mantle cell lymphoma, this is a UK and French study that’s recruiting. We did present some earlier data on our own experience with the combination of ibrutinib and venetoclax in mantle cell lymphoma and our conclusion is that this combination is tolerable and that we have seen some very promising responses in mantle cell lymphoma. Once again it sets the stage for taking these types of combinations forward in other histologies.
PH: We talked about MRD a moment ago but do you think MRD will be how we define duration of therapy with the combinations? To stop the treatments I guess would be the logical approach.
PG: Yes, probably that’s the… besides the fact probably we should first have MRD as a surrogate endpoint recommended at least in the clinical trials, allowed to be used in clinical trials in order to shorten the length of the trials because with so many good drugs, effective drugs, it will be difficult for the next generation drugs to show more efficacy if we don’t have a surrogate endpoint. Having said that, it’s also very likely, like in the case of venetoclax, that MRD can be indeed used to define a moment to stop and discontinue therapy. Rather than to use MRD to increase the quantity of therapy because that, of course, will also in the case of patients who remain MRD positive because there we need definitely more prolonged studies also to evaluate the toxicity, the additional toxicity that we can provide.
CF: I was just going to make the point that there’s also the health economic argument for combining agents perhaps on a shorter duration with an MRD defined stopping point which might have broader economic benefits.
PH: It’s a real challenge, the implementation of these new drugs into our treatment paradigms in CLL. What would you consider as being currently the standard of care for, say, front line CLL? Do you think the new drugs have pushed out FCR and chlorambucil plus antibodies?
PG: That’s a very nice question and probably we’ll be facing it in the next days, in the next week. FCR may remain a gold standard for a subset at least of younger patients without comorbidities. A number of studies from Italy, from Germany, from the US, have showed that indeed FCR can obtain long-term remissions above ten years in 80% of patients with mutated immunoglobulin genes. So maybe that would be another big change in the future so we will be treating patients in front line if young if they have mutated immunoglobulin genes with FCR. All the remaining patients which probably are the majority probably will benefit from the novel therapies. The same thing applies to the elderly setting where, of course, one can use chlorambucil together with monoclonal antibodies or ibrutinib now. There again probably it’s a decision that has to be taken together with the patient even because one may discuss about the possibility to have a treatment that lasts only for 6-12 cycles like with chlorambucil based therapy or a continuous treatment so that probably the quality of life of the patient and the life of the patients himself would be really important to evaluate which is the best therapy.
PH: Do you think that’s true globally?
CF: I’d agree with Paolo that today, at least in the UK, FCR would remain the standard of care for younger, sufficiently fit patients and the older FCR unsuitable patients, that’s where the novel agents are going to make the biggest impact in the first line setting.
CT: There are studies of ibrutinib versus FCR, phase III studies ongoing, and I really think that it’s up to ibrutinib and other novel agents to prove that they’re better than FCR in younger eligible patients.
PH: So at the moment it’s fair to say that in the relapsed setting and the refractory setting there’s the novel agents, certainly ibrutinib, have found their place and it creates challenges, of course, in terms of tolerability both physically and also financially but clearly are better than the conventional treatments. But then the front line we have a series of combinations both of antibodies in chemotherapy which are developing and also novel agents with either chemotherapy or with each other. So we’re moving forward very rapidly. So, as you heard, there’s a lot of interest in the treatment of CLL. Here in Copenhagen at EHA we’re seeing now advances in terms of novel agents coming along, evidence in front line and in combinations. So the field is moving rapidly but we do need to continue our clinical research to move towards our attempts to cure patients with CLL.
