JG: Hello, I’m John Gribben from the Bart’s Cancer Institute in London. We are here today at the twelfth International Workshop for Non-Hodgkin’s Lymphoma. I’m joined by my co-Chair, Myron Czuczman as well as other members of the scientific committee, Randy Gascoyne and Wyndham Wilson, and we’re going to summarise what we thought were the highlights of day one of this really exciting meeting. As usual I think this was, as always, a very enjoyable day but what I really enjoy about these meetings is the small format allowing lots of time for interaction and we certainly saw that today with lots of audience participation. What do you think were the highlights of what you took out of today, Randy?
RG: Well we heard, I would say, quite a large number of really good talks. I would echo the comments you made about the time for discussion. I think that folks out there need to know that what makes this meeting so unique is just that that, that there are didactic lectures but that we leave a huge amount of time for people to get up and ask questions and discussion amongst the participants. I thought it was outstanding; I thought there were large parts of the day that were outstanding. What did I think was the best? Well I thought our session, John, was absolutely outstanding that we did but, that aside, I’ll reserve judgement on that one and wait to hear what the others have to say. I thought the final session of the day that actually discussed peripheral T-cell lymphomas and some new developments was a very good session – all four speakers tremendous, gave us a really good update and a little bit of excitement about new therapies in the pipeline for T-cell lymphomas which is a huge unmet clinical need.
JG: What I found exciting in that session was, again, the histopathologists putting in context more work that’s coming out about the cell of the origin and the bit that we’re already understanding in B-cell malignancies, it’s finally coming together in T-cell malignancies also, that the cell of origin and the genetic underpinning of the disease provides rational targets and we’re beginning to see those rational targets hopefully starting to make an impact on what have seen as being a difficult to treat group of disorders until now.
RG: I fully agree.
JG: So, Wyndham, what for you, what did you take as the highlights of today?
WW: I certainly hate to say it, but I did think that the first session that Dr Gascoyne and yourself ran was really one of the highlights where you focussed on the microenvironment. There has been a lot of work in that area, or at least a lot of interest, which really dates back ten years or more. But I think that we’re now beginning to come up with actual actionable targets and we’ve always understood that there is inhibition of immune surveillance; strategies have been used for many years to try to overcome that, idiotype vaccine, they really haven’t worked. However, the whole issue with exhaustion of the T-cells and now having some of the new checkpoint inhibitors showing a fair degree of activity within solid tumours really represent some very good agents that can be used for lymphomas as well. I also enjoyed the large cell session as well. One of the things that really came up, and again this goes back to some of the work that Randy has been working on, that is the role of MEK and Bcl-2 in identifying poor prognosis groups within large cell. What really is important about this is that although they’re a relatively small group, when we look at the ones that have the translocation, at least with standard therapy the outcome appears to be relatively poor. Again, although it’s a small slice of the overall group, about 6-7% maximum, we know they do very badly with standard therapy and, for example, there’s a large ongoing multicentre trial using the dose-adjusted EPOCH-R regimen and an ASH abstract has been sent in. The preliminary results look extremely good that the EFS is looking in the 70-80% range even for double hits. So this really may represent the first therapy that might be very effective against this generally poor acting group.
JG: One of the things I found a little bit surprising from that session was the very different attitude that people had about thinking of how we should attack and treat that. Everyone accepts it’s a very poor risk group of patients but some people are still very conservative of believing that until we’ve got solid clinical trial data we should continue with the therapy that we know is ineffective. I was a little bit surprised to hear just how much disparity there was among the experts in the room about how we treat that entity.
WW: People can sometimes be nihilistic about it and that all the data comes from the fact that standard therapy has a very poor outcome. Again, there is emerging data using other more aggressive regimens where the outcome looks better. Retrospective series that have looked at Hyper-CVAD, have looked at transplant and now have looked at dose-adjusted EPOCH-R have all indicated that more aggressive therapy may be the way to go with these tumours. Perhaps it’s not unexpected in that MEK is really the core of molecular abnormality associated with Burkitt’s lymphoma and there we know that R-CHOP does very poorly and you need more aggressive regimens. All of the strategies that doo appear to be more effective, such as Hyper-CVAD and EPOCH are all regimens that are very effective against Burkitt’s lymphoma as well. So I think the parallel exists and I think that it’s very rational at this point to think about using some of these other strategies. Right now people are either using R-CHOP or they’re going to very draconian measures by taking some of these people to allogeneic transplant.
JG: Just picking up on something you mentioned before about the T-cell lymphoma session and then thinking about the microenvironment, there was no mention about the microenvironment within the T-cell lymphomas. Is that because we don’t believe that the tumour microenvironment is important or we just don’t know enough about it and it hasn’t been focussed on by individuals working in T-cell lymphoma? You see this down a microscope all the time, there must be a complex microenvironment occurring in that situation also?
RG: Yes, I think my answer would be twofold, John. There was a review recently actually talking about the immune microenvironment in T-cell lymphomas. One of the challenges we face with those diseases is actually separating the wheat from the chaff. We don’t really have very good ways to determine what cells are malignant and what cells are benign and that’s been a real challenge. However, I think the next gen sequencing data are going to help inform on that and I guess we have to walk before we can run, sort of thing, so I think we’ve got to understand the genetics of the tumour cells first and then understand the impact of those alterations on the microenvironment in these diseases. As I said, although there was a review, I don’t remember where I saw it, it was written recently, I think there will be a lot more data once we’ve resolved the genetics of the disease. People will then, the same way we did in large cell lymphoma and in follicular lymphoma, will then hopefully at that point turn our attention to thinking about the non-neoplastic cells. If I was a betting man I would bet there’s no question there’s very significant cross-talk between the benign and the malignant cells that could be very important in that disease. But we’re not there yet.
JG: So, Myron, what were the highlights you took from today?
MC: I just think that we had excellent presentations and what I did appreciate was, as we stated, there’s a small presentation, didactic, but the ability to appreciate the complexity but also the large number, the wealth, of novel potential targets that are druggable that we’re using now or actually we’ll be able to be developing in the very near future, it’s very exciting. Now, how to put them all together, as we discussed, is going to be difficult, whether it’s going to be concurrent, sequentially based on toxicities, and even unknown toxicities – sometimes we combine things that we think they’re going to be actually not very toxic and they are. But what’s interesting is that we also put an idea that when one does this, it’s not just because things have single agent, it has to be a thoughtful and a rational type of approach to this to assay, maybe, a mechanistic hypothesis and then going through and then testing it before we just start putting everything together as a big mix. I also do appreciate that this is definitely an international flavour and we do see that our differences of approaches, as we discussed in large cell with one of our sessions today, and it was asked by my friend Randy here that if you had lymphoma how would you treat it? We didn’t get the same answer from any of the individuals that were on the stage. However, I think we do have to appreciate there are multiple approaches but it is nice to at least have that kind of open discussion to see what are the pros and cons so that we can even open our own minds so we have our experiences ourselves but to learn from others, especially with the international type of different types of approaches, different drug combinations that we don’t use in the US but they use in Europe. I think that’s actually very exciting, that we all can get together with scientists, pathologists and look at the translational work and basic work and actually just open our ideas and maybe have some novel approaches that can be used when we set up trials, not only the actual clinical results but with people like yourself and Randy looking at the translational type of component, what type of other studies, correlative studies, that really have to be done in order for us to really better understand and improve outcomes.
JG: Now, tomorrow we’re going to talk a lot about individual novel agents but I liked in the mantle cell approach where we thought about a disease and you thought about what’s the current treatment, what’s the rationale for thinking what targets to bring in and how might we do that. So there’s two different ways of looking at it: one is about the drug but I liked the approach of thinking about the disease. I always like the approach that we have at these meetings about mixing together the pathophysiology with the disease so we can think rationally about bringing the right targets together. So that, for me, was one of the good features of the mantle cell session that you chaired, Wyndham. So, taking it all together, I think we’re all very, very happy with the way the session went today. I think what you’re hearing is that we all take from this meeting, that the important thing that we find, is the discussion that happens after short didactic talks; the ability to bring experts together from different backgrounds in terms of histopathologists, clinicians, working in different diseases and bringing that interplay together really makes this workshop so successful. So, another successful day in very hot Scottsdale, Arizona and we’ll be talking again tomorrow about day two on the workshop.
