Expert panel discussion: The best of iwCLL 2015
Prof John Gribben - University London and Barts, London, UK
Prof Michael Hallek - University Clinic of Cologne, Cologne, Germany
Dr Michael Keating - University of Texas MD Anderson Cancer Center, Houston, USA
Prof Kanti Rai - Long Island Jewish Medical Center, New York, USA
JG: Welcome to ecancer, I’m John Gribben from the University of London at Barts. I’m joined at the iwCLL meeting in Sydney by probably the most esteemed panellists you could possibly imagine in the CLL field, Michael Hallek who is professor at the University of Cologne and, of course, the chairman of the German CLL study group; Michael Keating from MD Anderson and, of course, the father of us all in the CLL field, Professor Kanti Rai. So thank you very much for joining us here today. Of course it has been very nice to have a meeting on the other side of the world, although a long way for us to come. So what has been your general view of what you’ve heard at the meeting and what are the take home points that you’re going to take away from this, Michael?
MH: My major point of this meeting is basically two things I’m impressed about. The first data coming out from combination of novel agents, kinase inhibitors, Bcl-2 inhibitors, antibodies, combining them gives us the potential of achieving more and more profound remissions, more complete remissions and I find this a very, very encouraging perspective. We now have, as I said, the first data that we saw, for example, from the Australian group with the combination of Venetoclax with an antibody and I think that’s leading the way into a very hopeful future for CLL research in the clinical setting. In terms of laboratory work I was most intrigued about a dialogue this morning by Cathy Wu and Carlo Croce about the different approaches, how to understand the pathogenesis of CLL by means of genetics and the genomic data analysis, so the broad use of sequencing. Carlo Croce made the good point that once we discover a mutation in a disease like CLL it doesn’t automatically mean that this has a driver function because you have to prove it by experimental steps that need to be taken carefully, including animal models, including studying that carefully. But both talks actually gave a nice view how we currently can understand the pathogenesis and the onset of CLL which is probably driven by early events on chromosome 13 that changes microRNAs. He made this point very elegantly and Cathy Wu basically now has an entire landscape of genomic aberrations that we are just about to understand in CLL.
JG: So presumably targets for new therapies that will come in the future and it’s by understanding the science that we really move forward.
MH: And also, to finish up on that, if we expand the cohorts, so enlarge the cohorts and investigate more patients for genomic aberrations we will discover more aberrations than we previously thought. It’s a very complex universe but there are new discoveries; even now, every year, we discover novel genes that contribute to the pathogenesis of CLL.
JG: Sure. Now, Michael, you’ve probably done more than anyone else in the field in terms of bringing together the chemotherapy drugs and the chemoimmunotherapy drugs into using a scientific rationale to find the right combinations. Where are we, do you feel, in terms of bringing the novel agents in? Are they going to be single agents, maintenance, are they going to be with chemotherapy or, like Michael, do you see novel novel combinations as the way we see going forward?
MK: I think there will be novel novel combinations. I think at the meeting, by and large on this occasion, we were criticized some years ago that we were only talking about the younger people, that was those less than 65 or 70. This meeting was dominated by…
JG: People our age!
MK: … discussion of the mature group or the hairless group, so that we’ve shifted over to a more relevant population. Fortunately the new agents are blessed not only with remarkable efficacy but a very manageable toxicity for the majority of patients in the short term. I think we really do need to collect data prospectively very accurately to figure out what’s happening in the long term because the tyrosine kinase inhibitors in CML, the reason we have so many of them is that so many of them are coming off one and going on to the other etc. so that it’s not going to be quite as easy. I think that one of the themes that really interested me was that up until recently we’ve been pushing to achieve MRD negativity, so no residual disease, and now we’ve shifted into, ‘Well let’s just control it. It’ll be OK.’
JG: And what do you think of that? You’re the person who moved the field forward most in terms of finding therapies that would get MRD negativity. For years you’ve been pushing the notion that we should use MRD as a driver to be thinking about other approaches. Do you think that’s where we need to be going with novel drugs to get people off these agents and be MRD negative?
MK: I always like to get rid of cancer cells, they’re not good to have around.
JG: I imagine, exactly, if you’re thinking that a drug… that cell is going to become resistant to therapy it’s going to become resistant to therapy but still there.
MK: Yes.
JG: It can’t be if it’s gone, right?
MK: And I think that one of the points was that there was a lot of discussion of the immunology of CLL but there was not much that was in place for rebuilding. There was some work at the NCI by Adrian Weistner talking about, OK, IgA is restored without IgG and M. It’s a question – how does that happen? A very provocative question, we can expand up T-cells and natural killer cells, etc, but we’ve always been dancing around the fact that the major problem that we’ve been addressing clinically is a low gamma globulin level.
JG: There were a fair number of talks on the microenvironment, about its importance in science and everyone thinking that it’s a good target but there’s not that much I heard that tells us that we’re actually doing that yet.
MK: I agree and I think that the TCL1 mouse model and the work that you did implied that CLL is a very dramatic inhibitor of stromal interaction, they just don’t work very well, so that the dialogue between the CLL and the stromal cell. And everyone has their little view of the stroma but the stroma is basically the whole body. You know, we have exosomes floating around
JG: Especially the point you made in CLL, the cells are everywhere. Yes.
MK: Everywhere and they go where they want.
JG: Sure. Now, Kanti, one of the themes from this year’s meeting was that the young investigators’ meeting that started as a small offshoot of this meeting several years ago is growing and growing and becoming a major focus. Obviously it’s exciting to see young people coming into the field but what did you think of the notion of them having a separate stand-alone meeting? People could say that maybe those people should have had the forum to present their work to the whole meeting, so what’s your view about having that separate meeting versus having some of those young investigators more integrated into the meeting?
KR: Well John, this Sydney meeting has been a great revelation to all of us, the so-called old-timers working or students of CLL that I feel that the young investigator meeting forum is relatively young in the studies of CLL and it has very impressively matured in a relatively short time, starting a number of years ago at iwCLL in Brooklyn but then really taken over in a very methodical and effective organised manner by Dr Michael Hallek in Cologne. Since then, young investigators have been looking forward to every two years a gathering of CLL people and they have shown, particularly this past Sunday, that young investigators are making enormous contributions. They do not need patronising by the older folk but they are still necessary to be identified because they get stimulation by the presence of their older mentors. But their intellectual power, their technological power and their clinical powers are really phenomenal so we come away with a great degree of encouragement, excitement that the future of attack on CLL is going to be in safe hands. And this meeting, particularly for young investigators, and expanding into non-age group of investigators, has been that we emphasise for the first time that Asia has major ideas and contributions. For example, we have presence both in young investigators and not young investigators of China - they made tremendous contributions. Japan, Malaysia, Singapore, India, Hong Kong, and those are the things that are opening the CLL doctors’ minds that even though incidence-wise much less than the Western World but the questions of CLL in Asia are very, very critical to understand the disease better. I think if we did not have a young investigator forum we might have missed it altogether.
JG: Sure. I guess the other thing that I’m picking up from the young investigators’ forum is that it isn’t just a day at the meeting, it’s a network with which these people are able to work with each other between the meetings, so a real opportunity for them to have discussions and start to have the kind of relationships that we’ve built with each other over the years, not just in your own institution but across institutions.
MH: If I may add a little point on this because I think it’s so important. Some of the now leaders, young leaders I would call them already, I would name a few like Con Tam here also. They have been attracted to the field by the young investigator meeting a couple of years ago and I think it’s a beautiful thing to watch that we can actually integrate novel ideas into the iwCLL. So I’m very happy that the young investigator meeting is so well established now.
JG: Now, do we have a location for the next meeting?
MH: Yes, it’s going to be New York.
JG: New York? Back to New York? OK.
MK: For the iwCLL, the next young investigator, is that going to be in Germany?
MH: In Cologne next year. So when we have a smaller workshop. So the young investigator meeting is annually pursued andthat will be in Cologne and the iwCLL next meeting is going to be in New York, led by Nick Chiorazzi.
MK: One of the things that I’ve been thinking and talking with Stephen Mulligan, because of his connections, to have an extension meeting of the Asian investigators in Asia. So some of the people in the iwCLL Association go over there to their place and establish these connections that we do get in these various meetings. The CLL Global Foundation will contribute generously towards establishing that next year.
JG: I guess you’re right, I guess the very fact that the disease is less common means that individual clinicians have much less experience so there’s even more of a need for real expertise for diseases that are themselves rarer within those communities. It will also be fascinating to see whether there really is anything different in the biology on the basis of the genetic background on which it’s occurring at a lower frequency. I think that will be fascinating.
MH: That’s something we have not really uncovered yet, why parts of the Asian population are so nicely protected from getting CLL.
JG: Maybe there’s something there we could learn.
MH: We could learn or have to genetically see. Then the other thing I learned, actually, is their awareness for hepatitis, both in terms of actually avoiding risk because it’s a real health related problem in the Asian countries, much more frequent, so that they really screen before starting antibody therapies and really do very careful prophylaxis which we actually tend to neglect, eventually, sometimes. And also the question that I got asked and I think is unsolved – how much HCV and HPV contribute as antigens, potentially antigen drivers, for CLL. So they actually have the hint that in their countries it’s strongly related with age and former history, so we don’t know whether that’s true but it’s an open question that I think we neglected a little bit.
JG: Sure, and at least now it’s being investigated.
MH: Absolutely.
JG: Well what you’re hearing, of course, is that we were all very excited by the meeting we’ve had here in Sydney; we’re all looking forward to the next meeting. We’re really excited that the young investigators are starting to work in this field which means that the science and the clinical translation that we all believe is so important to come from this disease will continue into the future in very good and very safe hands. We’ve certainly enjoyed the meeting and I hope you’ve enjoyed hearing our overview of it.
