ASH 2014: Expert discussion on the latest in CLL

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Published: 7 Dec 2014
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Prof John Gribben and Prof Stephan Stilgenbauer

Prof Gribben (Queen Mary University London, London, UK) and Prof Stilgenbauer (Universitätsklinikum Ulm, Ulm, Germany) review the data and opinions arising from ASH 2014 about the treatment of chronic lymphocytic leukaemia (CLL) for ecancertv.

The experts offer a comprehensive analysis of the current treatments of the disease, noting the importance of cytogenetics and the unique genetic characteristics of individual patients. They also touch on some of the key highlights presented at ASH 2014.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

ASH 2014

ASH 2014: Expert discussion on the latest in CLLL

Prof John Gribben – Queen Mary University London, London, UK
Prof Stephan Stilgenbauer - Universitätsklinikum Ulm, Ulm, Germany


JG: Welcome to ecancer. We’re here on the first Saturday of ASH from a very wet and rainy San Francisco on Saturday 6th December. I’m John Gribben from Bart’s Cancer Centre in London and I’m joined by my very good friend Stephan Stilgenbauer from the University of Ulm and from the German CLL Study Group. So we’ve had our first CLL session already; on Saturday it’s usually just educational sessions but here we’re going straight into new data. A lot at the first session from the German CLL Study Group, as we’ve become used to seeing at these meetings. So the first talk today, in fact, was Barbara updating the preliminary data that she presented at last year’s ASH on CLL10, that’s the trial comparing up-front FCR from BR. What’s your interpretation of the data that Barbara updated us on today?

SS: Thank you John. CLL10, as you said, was a large trial; I wouldn’t consider it so much a German CLL Study Group trial but it’s a co-operative effort, isn’t it, comparing, as you said, in a randomised fashion BR against FCR. It was designed as a non-inferiority trial aiming at the proof that BR is as efficacious yet better tolerated than FCR. In the end the results that Barbara presented today made everybody happy because, on the one side, there was the proof that FCR is more efficacious yet on the other side there’s the proof that BR is better tolerated so in the end it’s a trial that in the beginning sounded like maybe a bit of boring design but in the end could really be practice changing in the sense that now the issue is settled and in fact it is settled with something that we didn’t want to go back to, namely an age cut-off, to determine which treatment is better and which is worse.

JG: So I see that, on the basis of CLL10, your next planned trial looks to be using FCR for the under-65s and BR for the over-65s. As you say, a little bit of a difference from the German CLL Study Group who have, of course, pioneered the use of SEER rather than age as a cut-off point. But here you're doing a little bit of both: you’re taking the good SEER risk patients and then making a subsequent breakdown on the basis of age.

SS: Right. The more important prerequisite was that CLL10 still included only fit patients, as determined by the SEER score and by renal function, and among them determined if FCR or BR was more efficacious and better tolerated. Going back to the fact one has to say that only among fit patients you can say the ones younger than 65 in age should be treated with FCR because clearly there is better efficacy and the treatment is well-tolerated among them.

JG: I interpreted the way Barbara was presenting it that there was the issue, of course, about getting a full six cycles in to some of the over-65 year olds and that getting six cycles of BR was potentially better than getting an incomplete therapy with FCR. Is that how you interpret what happens to that slightly older age group?

SS: Absolutely. The difference is that, indeed, in the elderly patients FCR was simply not tolerated as well as BR was and efficacy wasn’t that much different, possibly due to the fact that you could get more treatment into these patients. On the other hand, I think one has to say this trial is also remarkable in the sense, or different than many of the previous trials that we had, that it captured AEs over a long time, actually for the whole study duration. That is why the AE event rate and also severity looks much higher than in many other trials that we had previously, although it is looking at a realistic picture because what is interesting to us is not only the AEs over a six month or twelve month duration observation but really over the whole disease history of the patient. So that is a realistic way to capture it.

JG: Again we saw the importance of achieving a CR in terms of the outcome of the patients, which leads, of course, on to other data that we saw presented today in terms of thinking is the goal of our therapy, and certainly at the moment I think it is the goal of our therapy for young fit patients at the very least, to be really pushing towards eradication of minimal residual disease?

SS: The difficulty becomes that with these treatments in the first line setting, at least in the average patient, there is really great efficacy and we achieve CR, so we achieve long progression free survival. The marker that really tells us probably better, at least immediately after therapy or a short time after therapy, what long term outcome may be is minimal residual disease determination, or MRD, which probably, when you look at the data that was presented today, represents better than the classical clinical response criteria how much disease burden and how much risk of disease progression remains in the patient. Because, as we all know, PR can not only result from persistent disease but also from bone marrow not being determined or residual that could be from other causes than CLL.

JG: But do you interpret the data still to be saying that with FCR-like therapy for younger, fitter patients going towards minimal residual disease should be the goal of our therapy?

SS: At least it tells us that MRD negativity determines that your long-term outcome will be favourable. I don’t know if in turn you could say if a patient is not MRD negative after the standard treatment that we apply there is no proof so far that trying to achieve that by whatever other measure we have in hand that this will improve his long-term outcome. So the data are still a bit unsatisfactory from that point of view.

JG: Some of the reasons, of course, why the data is a little unsatisfactory is our assessment of what we mean by MRD negative remains a little bit nebulous. Now, almost presented less in the study but discussed more in the discussion afterwards was the issue about what’s the right tissue to look at. Should we be looking at peripheral blood? Of course bone marrow is a better source to look but are our patients going to allow us to have serial bone marrows done in a way to look at an analysis and how do we apply that kind of issue to outside the clinical trial setting?

SS: Absolutely, we have to be aware of the fact that the data that we discuss have been determined in a highly select population of patients enrolled on trials and agree to all these things that have been done. To make this applicable to the general situation and to be really practice changing it must be something that can be applied in general practice. The point is well taken that determining MRD in bone marrow is a much stronger prognostic factor than determining it in blood only. However, we need to come to the point that one bone marrow analysis is enough to determine outcome because, as you say, serial marrows is certainly something that we want to avoid at all means.

JG: Now, of course, that raises the next issue, that is if we do find, in fact, that a patient is MRD positive at the end of therapy, what more should we be thinking about doing if we really believe that is a surrogate for subsequent relapse? And the whole issue of maintenance and consolidation in CLL has been a difficult one for us to evaluate for a long period of time. We did see some data today on the use of our ofatumumab maintenance type therapy, not in the up-front setting but in the relapsed setting. What’s your interpretation of that data that was presented today?

SS: The whole picture that we look at at the moment is that still in the front line setting we use chemo-immunotherapy, be it FCR or BR, and then look what outcome may be. We are all very much aware of the fact that we have new agents licensed, at least in the relapsed refractory setting, but also for subgroups of front line patients that may change the whole picture. However, we may come back to that in another session on the new agents. In the session today, as you said, there were two presentations on maintenance treatment with antibodies, rituximab from the Austrian group and ofatumumab from the HOVON Nordic group, that actually both showed quite consistently that you can prolong progression free survival, possibly also time to next treatment. However data on overall survival or changing, really, the natural course of the disease have, at least with the follow-up that is available today, not really been presented or at least, from my point of view, not convincingly demonstrated that there’s an overall benefit from these maintenance strategies.

JG: So at the moment it’s obviously still a question for clinical trial evaluation and not one which we should be practice changing on anything that you saw today.

SS: Probably prolonging progression free survival with antibody infusions is a nice goal to achieve. However, as you said, the trials were done in a setting where we have already approved novel agents that, to me, look like agents that are better tolerated than continuous antibody infusions and possibly even may result into better disease control than antibodies.

JG: Now the one group of patients that have historically not done well with conventional chemotherapy have been the patients with 17p deletions. Your group are the world leaders in terms of the assessment of the genetics of CLL. We saw some quite intriguing data today, a little bit slight different twist on what I’ve been used to having been brought up to think about in terms of 17p itself conferring the chemoresistance. So the question about the more complex karyotype being in fact a more prognostic marker, now I find that study, myself, a little difficult to fully interpret. So what did you take from that study?

SS: The study presented by the MD Anderson investigators today on their cohort of patients treated with ibrutinib based regimens pointed to the fact that, yes, there is a high incidence in this high risk population of 17p deletion and very, very much correlated to that there is a high incidence of patients with a complex karyotype. I think the data are instructive and they should inform our future research on that question. The point obviously is what comes first, p53 abnormality, would that lead, as it is scientifically conceivable, to genomic instability and complex karyotype or is there first, by some other predisposition, a complex karyotype then leading to p53 abnormality? I would prefer probably a thing that makes biological sense in terms of p53 being first and then genomic complexity resulting. A caveat to the study that was presented today is that, a mixed bag of different treatments, that we’re not only ibrutinib based but also involved chemotherapy, involved antibodies. So our heterogeneous patient population was studied and it is, as I said, certainly a point that is worth noting. If you have the data available it may inform your decision even if you discuss about an allogeneic transplant with a patient or not because the response to novel agents appears to be shorter, no matter if the 17p deletion is present or a complex karyotype is present. So I wouldn’t really weigh them too much against each other but both of them inform us that probably outcome, even with the novel agents, is inferior in these patients.

JG: Not something that was really discussed today but in terms of the complexity of these issues where do you think the conventional karyotyping versus next generation approach is in terms of looking at copy number alterations and mutations? Is that where you think the field is going in terms of us understanding the underlying biology of complex karyotype CLL?

SS: Right. It’s still interesting to see that something you could almost call old-fashioned like conventional karyotyping is a strong marker. However, the resolution of karyotyping doesn’t really illustrate to a full extent what the real molecular mechanisms or underlying pathogenic principles are. As you say, we need further studies by next generation sequencing or other sophisticated molecular tools to really come to the cause of all these events because what we see in the karyotype is probably just the train wreck of something that happened earlier on or predisposed a patient to develop that type of resistance mechanism. This should be the aim of our further investigations.

JG: OK, so what you’re hearing already is that we’ve had a very exciting day thinking about CLL, even on our first day here. In many respects we thought this was the session that had maybe the less intriguing data, the novel agent therapy we’ll discuss on another day, but enough very interesting data coming out today for lots of us to think about. So thank you very much for coming here, Stephan, and I hope you enjoyed the session.