iwNHL 2013

Meeting highlights from the 11th iwNHL 2013: Day 1

Prof John Gribben – Bart’s and Royal London School of Medicine, London, UK
Dr Randy Gascoyne – British Columbia Cancer Agency, Vancouver, BC, Canada
Dr Wyndham Wilson – National Cancer Institute, Bethesda, MD, USA
Dr Myron Czuczman – Roswell Park Cancer Institute, Buffalo, NY, USA
Prof Michael Pfreundschuh – University of Saarland, Homburg-Saar, Germany

JG: Welcome to the eleventh international workshop on NHL. We’re here in Dublin, I’m here with the Scientific Committee of the meeting and we’re here to talk about the exciting new developments we’ve heard about today in the first day of the meeting. So we started off with a fascinating session looking at both the biology and the clinical treatment of some of the difficult T-cell lymphomas. Randy, you’re our pathologist here, what was Laurence de Leval telling us that was of importance to the clinician in the understanding of these T-cell lymphomas?

RG: Good question, John. She started out with a very good overview of both ATL but also ALCL. A lot of insights are coming from a significant improvement in the understanding of the biology of those diseases. I’m not sure at this point they translate into meaningful choices for alternative therapies but certainly the kinds of studies being done that have shown us, for instance, that there’s a clear association between AITL and what are known as follicular T helper cells has certainly come to be quite evident from all the work that’s being done. But I think it’s early days yet to know that there’s going to be impacts for treatment or improvements for patients. There are a number of groups that we heard about, actually, although not present at this meeting, that are actually sequencing these tumours and sequencing at depth. I think that kind of investigation is going to lend itself to some novel insights into these diseases.

JG: We’ve been stuck on CHOP-based regimens and knowing that those are unsatisfactory, particularly for the poor risk subgroups that were discussed in particular in this session. What were you hearing about that excites you about thinking that we’re on the brink of a paradigm shift of seeing something moving away from where we’ve been to a more risk adapted strategy based on understanding the biology of the disease?

WW: I think one of the difficulties with the T-cell lymphomas overall is that they’re simply very rare. So it’s been very difficult to both get numbers as well as to identify targets. Probably the best and most exciting examples are the anaplastic large cell lymphomas. As you all know they come in those that have translocations of the ALK kinase and there are now some specific inhibitors of that; both in phase I trials and in some retrospective studies involving phase II doses there have been very high response rates in relapsed, refractory ALK positive ALCL. So I think that is a very meaningful advance and although these are diseases that can be cured with conventional CHOP chemotherapy, the up-front cure rate is still only around the 60-65% range. So the addition of agents like this would probably increase the up-front cure rate but that’s yet to be found. The other interesting thing, I think we’ve come full circle here, is the fact that there’s a lot of shared biology between the ALK positive and the ALK negative ALCL. At one point they used to be considered in the same grouping and then they were separated in the last WHO but there’s emerging evidence there may be alternative activation of some of the downstream ALK kinase targets so that they may have more shared biology than people think. That really brings us to the idea of do they do that much worse than actually ALK positive ALCL. With aggressive chemotherapy regimens to me it’s not clear necessarily that the difference that people have seen in the past would still hold. So I see a lot of favourable things. Then, of course, there’s the brentuximab, which is a monoclonal antibody anti-tumour agent conjugate that people are very excited about. Interesting drug, not a major breakthrough insofar as it’s still dependent on an agent, a … agent, the class of which has been well known to be active within these tumours for many years.

JG: Can I just come back to you in a sec. The issue of sub-classifications within the more recent WHO classifications which more and more are looking to be based on cell of origin. But also, of course, clinicians are looking to group diseases together in ways in which we will understand we would either treat them in a similar way, particularly based on biology. So your view on whether the classification was the correct way round to be thinking of these diseases and different entities?

RG: Very good question, John. So in 2008 the WHO made the choice to distinguish ALK positive from ALK negative and determined ALK negative to be a provisional diagnosis. They did that largely on the basis of a single survival curve difference that looked impressive and looked meaningful. But there were a lot of people who were a little bit sceptical about the way in which that was done and, as we heard from Dr Leval, there are some growing data and I would argue some fairly compelling data that actually suggests, as Dr Wilson just said, that there’s a rethinking of this now and there may be more common biology. We not only heard about the possible coming together of both ALK positive and ALK negative ALCL but even about this fairly large subgroup of CD30 positive peripheral T-cell lymphomas that also seem to share some similarities in biology. So I would guess that the next iteration of the WHO may look a little different and I wouldn’t be surprised if that provisional diagnosis in some way disappears.

MC: Yes, John, just the comment that with respect to the ALK positive, ALK negative anaplastic large cell lymphomas is that there was this interesting discussion about maybe that they’re more similar than different. However, it’s been standard practice, and that was also discussed, that most patients in US centres with ALK negative ALCL after undergoing induction therapy will go directly to autologous stem cell transplant. I think that we always talk about personalised or individualised medicine, we have to start doing what we’re talking about. What that means is that, I think Francine Foss also mentioned, it’s not just ALK positive and ALK negative, that you can also with a number of these peripheral T-cell lymphomas look at the IPI, that the IPI, whether you have ALK positive or negative, may be a more sensitive measure about patients with respect to their prognostic outcomes. So we have to not just say one treatment fits all, we start have to be utilising that, and with respect to therapy, as mentioned by Wyndham with respect to brentuximab vedotin, although it’s maybe not exciting, it was interesting that patients with ALK positive or ALK negative do similarly just as well, we’ll say. So it looks like maybe with these new agents we’re not going to have such a clear distinction between this is going to be only for this or that. In addition to that, as mentioned, you had the chemokine CCR4 antibody, that has been actually approved in Japan which still has a couple more years to go for being analysed in the US, but I think that’s also a very promising agent. It’s not going to be curative but also adds to our armamentarium. One other thing we mentioned a lot was about the microenvironment. We are just beginning to investigate the possibility of using agents such as lenalidomide with respect to the treatment of T-cell lymphomas as well.

JG: Michael, the German study group has always had a large interest in looking at the T-cell lymphomas but we’ve also heard about the relative rarity of these tumours and the subtypes. How do we work together to ensure that we get the trials done in as rapid a way as possible in the right subgroups of patients? Can individual countries continue to do this or do we really need to look to international collaborations to get these rarer subtypes of diseases studied the way that we’d like to see them?

MP: Yes, I think with the rarer subtypes we cannot achieve much on a national level and meetings like the one here should also be a basis to start co-operation over the borders. With respect to the T-cell lymphomas for me it was quite interesting, so far we have neglected the ALK positives because they are doing so well with CHOP and now realising that they are much more similar clinically if you look at it on the IPI basis but also molecularly; this will help us in a large number of patients that we can try new targets on. So this was quite helpful and should really change our daily life and the practice within global trials.

WW: I did want to bring up one interesting idea. We always think about targeting a protein that is activated or somehow turned on. The situation of ALK negative ALCL is a very provocative setting in which you could consider possibly that even the normal activity of the ALK kinase could be operating and there could be amplification processes downstream such that there still may be some activity of a drug like crizotinib which is an inhibitor in ALK negative cases. I don’t know if that’s ever been looked at but we need to expand our view of how we should look at targets. I think a good example is BCR signalling where there may be baseline BCR signalling but there may be amplification processes going on downstream such as inhibiting BCR signalling even if it’s not itself mutated the actual protein that you would want to target that. So if people did that and it did show some activity it would further the idea that these two, ALK negative and positive, have shared biology.

JG: The next thing we heard this morning was moving on to another controversy, that is the management of paediatric versus adult patients. We’re all very well aware that the paediatric patients, as we see in acute leukaemias, doing very much better in terms of outcome than our patients. There’s the issue of is it the biology of the disease that’s different and is it the treatment regimens. Given that we see treatment regimens that are different and we see what I believe are probably differences in biology also, what did you take from the discussion? Quite often it’s the case that we’ve been trying to take from the paediatricians’ approach but was there anything you heard from what Cath Bollard presented that would make you think that we should be, for instance, doing more CNS directed therapy or altering our approaches based upon what the paediatricians are doing?

WW: You’re looking at me, Dr Gribben?

JG: I’m looking at you to try and be controversial right

WW: Absolutely. I would say that no, we haven’t learned anything from the kids but I do think that the paediatricians could learn plenty from the adults. Let me put this into perspective at least for the lymphomas we’re talking about, Hodgkin’s lymphoma and the aggressive B-cell lymphomas. These diseases are much more common in adults than they are in children and there has been extensive understanding of their biology of effective treatments in adults. Therapies in adults have really evolved specifically to treat those diseases. A very different model has been used in children; because the very first curable diseases in children were acute leukaemia the chemotherapy that was used was very aggressive, intensive therapy and they have then basically taken those backbones and applied it to these other diseases and found that they had good outcomes and then are now trying to dial down from what is extremely aggressive therapy. I think dialling down is a very good idea and they have reduced some of the side effects but they’re still facing side effects, long term side effects, that are very severe. They probably could learn a lot from some of the adult regimens that show very high cure rates in adults in general; even in paediatrics when they’ve looked at outcomes they find that the older children don’t do as well as the younger children. Therefore, adults with similar diseases are probably harder to treat than the younger children with the similar diseases. If we are, in fact, getting extremely good at outcomes in adults with our regimens that are much less toxic, I think there should be a quicker move by the paediatric groups to move those down into the paediatric setting.

JG: It’s always been difficult for the paediatricians to wind down. All the paediatricians that I speak to know that they’re probably over-treating most cases of acute lymphoblastic leukaemia and are over-treating most kids with Burkitt’s and with diffuse large B-cell lymphoma. But how do you approach a parent and suggest that you give less therapy and expect those parents to be able to want to enrol their children? It is a difficult dilemma that they face isn’t it?

WW: I don’t really see the parents as really being the obstacle here, I see the doctors as being the obstacle. I say that because, as an adult oncologist that treats many of the same diseases that occur in kids, we have had these protocols – accept children down to the age of 12, and when we explain the outcome of these regimens in adults, their toxicities, and show them that the results in adults are very good, we always have sign-on. So I don’t see this as an issue, I think it’s the doctors that are unwilling to move.

JG: I was very struck by the fact that they’re focussing their decreased toxicity on the decrease of the CNS treatments compared to irradiation rather than thinking of what the toxicity of the CNS directed treatment could be versus not needing to give any CNS directed therapy for groups, in fact, in whom the CNS relapse rate is actually incredibly low.

MC: Perhaps the relapse rates are low because they do give a significant… They don’t base it, I don’t believe, on potential risk. For example with large cell lymphoma we know that certain patients based on where they’re presenting at there are areas, there are regions, where we know that the disease might be at higher risk of developing CNS lymphoma but in the private practice in the community in the States often physicians basically don’t give it. Whether it’s because it’s a hassle giving intrathecal therapy in a busy practice, but the guidelines, in the NCCN guidelines, we do recommend whether it’s breast, testicular, perispinal, that CNS prophylaxis should be given. I think the issue that comes up is that unfortunately we see a lot of secondary CNS and a lot of work has come out from Michael and it seems like maybe there’s been a decrease with the utilisation of IV rituximab but I still think we see too much of secondary CNS lymphoma. Somehow, maybe by analysing it more effectively, Wyndham, with using flow cytometric techniques versus just cytology we can actually more better be able to pick up patients with really asymptomatic CNS involvement and treat them more effectively. But I agree, and I work with Dr Matt Barth, a paediatric oncologist who works in the laboratory with us and I asked him the same question: what took so long to get rituximab when you had a CD20 disease? He just said, ‘It goes slower with respect to the children’s oncology group. They’re more concerned about toxicity.’ But when I look at targeted therapies I don’t feel that we’re having signals that there are going to be long-term issues and they are less toxic than just straight chemotherapy with non-specific toxicities. So it is a bit of a quandary why they don’t accept it earlier and quicker. It seems like what happens when I ask them, it seems they have to do their own slow studies before they implement it and accept what we see in adults into the children.

MP: I think they could learn a lot getting our data of the young patients, up to 35 years of age, because I think there is not a border below and above 18, it’s a continuum. By looking at our data, patients up to 35 years of age, the results are as excellent as they are among the children because it’s only after 35 years that the results are getting worse. Whenever they talk about the results in adults they are speaking about people or patients who have a median age of more than 50 years. If you look at the younger adults, up to 35 years of age, our results are so excellent with much less toxicity than the paediatric protocols have that they should really look at our data and take the consequences. Where it is most obvious since we have introduced rituximab in the young population we have hardly any patients with CNS disease anymore. I am convinced that even the intrathecal methotrexate will have some late effects in these children, it’s a growing brain and I think there is enough data that the cognition is worse in patients who have received the intrathecal methotrexate as a child.

JG: Randy, in acute leukaemia it’s very clear that the translocations … therefore the basic biology of acute leukaemia is, in fact, different and changes not as a cut-off point but as a continuous spectrum with age. But I wasn’t hearing anything yesterday suggesting that we know similar things to be different about Burkitt’s or diffuse large B-cell lymphoma in the children.

RG: No, I think the wealth of data would suggest, although it always comes up whether or not there’s a different biology going on. For some of the diseases you just mentioned, Burkitt and probably most cases of large cell lymphoma, there are no really compelling data to suggest it’s a fundamentally different biology. However, that said, the Germans a year or two ago described a novel translocation that does appear to be highly enriched within younger patients. I’m totally blanking now on the nature of that translocation but it was work from Reiner Siebert in Kiel. But I think overall the biology is still thought to actually hold true and that lessons we learn from adults can be applied to kids and vice versa.

JG: So staying with biology, of course, and biology of diffuse large B-cell lymphoma, the first session after lunch today was focussing on the biology and treatment of diffuse large B-cell lymphoma. Again we had a couple of very basic principles, talks both from Ricardo and from yourself and then more clinically related talks from Myron and Michael. What I like about this meeting is the interplay between the biology and the clinical components. So Ricardo presented some very new data, in fact just appearing in Nature Immunology. So what were you talking from what he was presenting?

RG: I think the mutational landscape of large cell lymphoma, diffuse large B-cell lymphoma, is now pretty much established. What Ricardo does very well, and he showed us that yesterday, and you’ve made mention of a paper that actually I just downloaded while I was listening to his talk because it’s just out in the October version of Nature Immunology, is that he is extremely good at taking a basic observation of a recurrent mutation and from that developing a functional story. What that does is it adds texture to the biology and our understanding. Again, what he described as recurrent mutations in MEF2B were actually originally described by the Vancouver group and what he has done now is worked out the biology of that to show that they’re hotspot mutations and that what the effect actually is is an interaction largely with BCL6, a fundamentally important transcription factor within the germinal centre. So, to be honest just enlightening on that biology starts to distil down now upon the possibility of targeted therapies related to those recurrent mutations. I think that’s where the field needs to go so I think the number of other targets that have been shown to be recurrently mutated are beginning to go down that path. Another very nice example, I dare say, is work that comes from Vancouver again and that was the description of recurrent mutations in a gene called EZH2. That was described in February of 2010 and in less than three years there are five major companies who have specific inhibitors to that mutation. That material or, I should say, those small molecule inhibitors have gone into patients, as far as I know, as of June of this year. So already we’re seeing the fruits of that labour and I think the field will go that way. We will begin to develop targets to some of these agents and if they have a favourable toxicity profile we’ll begin to go into phase I and II trials and I think could absolutely revolutionise our therapies for this disease.

JG: Now that’s opportunities and it’s also problems. We’re already thinking about diffuse large B-cell lymphoma, ABC versus GCB type, but what we’re hearing at this meeting is that... and we’ve always known it’s a very heterogeneous disease and it’s a very heterogeneous disease at the molecular biology level, suggesting that there may indeed be some common pathways that are going to be targets but there may also be very small subsets. So then we’re back into the issue of how and what’s the right way to do these sorts of clinical trials. Do you use these agents in a take-all type study or do you really target that therapy? If we do so, how do we, as groups, work together to take very small subsets of patients? What are the mechanisms we’re going to have to do to have robust ways of identifying who those subsets are and is that a priori a requirement for entry into the sorts of clinical trials we’re thinking about? So, Michael, how do you think about that when you’re planning your studies going ahead?

MP: The problem is we need a robust test to define these subpopulations and if that’s available with respect to the ABC type and GCB type, the immunohistochemistry hasn’t helped us much so we’re waiting for new methods and tests that are more reliable, more robust. Nobody would have a problem to get these patients out of the large trials and bring them into an international joint effort because the numbers are small, they wouldn’t have the large population that we need now in diffuse large B-cell lymphoma to demonstrate further improvements where we are now up with 80% overall survival. Then we should have these joint efforts for the subgroups and put them on an international level.

JG: Thinking of tests that we should have, perhaps, more robust, you were talking about double hits and triple hit lymphomas and we’re talking about the lymphomas we can cure, but thinking of the groups that we already know have very poor prognosis. So it’s quite difficult for the clinician to know exactly where this whole field fits and how we should be thinking about these differently and how we target even the groups that you were discussing, so these so-called double hit and triple hit lymphomas. So, Randy, you talked about that in terms of presentation. What have been the issues in terms of us being able to interpret even MYC protein level expression within diffuse large B-cell lymphoma and use it and incorporate it in a way that is clinically meaningful?

RG: Sure, so I think there are some obvious issues there. I think, and I stated yesterday, that I believe we should be doing MYC as a FISH test on virtually all de novo cases of DLBCL. It will be found in roughly 10% of cases and the data are compelling that it travels with an inferior outcome in patients treated with R-CHOP. The issue is always then are there obvious alternative therapies, targeted or untargeted, in particular dose intensity would be the question. I think there are some preliminary data and Dr Wilson’s favourite regimen shows some significant efficacy in that group. So, again, those are things that are testable and we need to be thinking of. So at a basic level I think we should be doing FISH for MYC and probably also BCL2 and BCL6 on all cases if it informs on a treatment decision. The issue about immunohistochemistry is both important but still controversial. The importance is that if you stain for MYC and BCL2 you identify one-third of DLBCL all comers and it has been shown now in six separate studies, five of which are published and a sixth study that I’m not sure where it’s at in the publication process, hopefully successful, that have all shown the same consistent theme that the cases where the cells express both of those proteins, MYC and BCL2, accounting for a third of cases, clearly travels inferior outcome. But, as Michael has nicely pointed out, the problem we still have is that is an immunohistochemical measurement. Now, my own bias is that in spite of that those are the two fairly robust markers and I think that what we need to do is come up with some guidelines on how the tests should actually be done and how we interpret the results in terms of different thresholds etc. I’m not sure it’s ready for prime time but…

JG: You’re implying there that there’s something different about a translocation event rather than another mechanism of amplification of expression of the protein. … do we know…

RG: Well we don’t know but I think at the end of the day what became clear from that talk, I hope, is that the tumour cells are smart, they have multiple ways to deregulate the expression of MYC of which a basic translocation is one of the mechanisms. But at the end of the day the phenotype is going to be determined in any patient by the actual functional expression of a protein. So if MYC is there immunohistochemically and it’s positive, I don’t really care the mechanism by which it’s deregulated, I do at a level of biological understanding. But from a clinical perspective if a third of cases express both MYC and BCL2 and that travels with inferior outcome, that’s a meaningful data point.

JG: You talked about how rituximab has clearly changed the landscape in diffuse large B-cell lymphoma but of course you also presented your data on how little we sometimes know about the way that we’re using a drug that you’d think by now we’d have a very good handle on how to optimise its use.

MP: Yes, I think the way we give rituximab in diffuse large B-cell lymphoma is not based on a rationale, it’s for logistic reasons and for historic reasons. So we looked into this issue and we found that, the first observation was in elderly patients, that the males benefit much less than the females from the rituximab. So we looked into the pharmacokinetics, found out that the females have a much slower clearance, the elderly females than the males. And because of the slower clearance they have higher CM levels and prolonged exposure times and we think that’s the reason why the elderly females are benefitting more from it. Now we extended our pharmacokinetic studies to younger patients and we can see that both the young males and the young females have much highly significantly faster clearance than the elderly females. My consequence is that we must expect that all but the elderly females are suboptimal dosed once it comes to or you have to fight a large tumour load. The low tumour loads the results are so excellent we don’t have to change anything but patients with a fast clearance, low CM levels of rituximab and a high tumour burden we can really improve upon it by either extending the exposure time, increasing the dose and really get out the full potential of rituximab. So far the full potential is only being exploited in elderly females

JG: Should we be developing assays and measuring rituximab levels and dosing? Dose adjusted rituximab included in the dose adjusted epoch.

MP: I don’t think we need it because the therapeutic window is so large that we can easily increase the dose or the exposure time without running into problems with toxicity.

JG: So one of the agents that’s looking very interesting to bring into lymphomas, and into subsets of diffuse large B-cell lymphoma, is lenalidomide. You’ve done a lot of that work, Myron, so where do you think lenalidomide now sits in terms of our thinking about the treatment of diffuse large B-cell lymphoma?

MC: At this point particularly there has been data with respect to lenalidomide as a salvage regimen in patients with relapsed refractory large cell. It seems there’s a stronger signal with respect to the non-GCB or the activated B-cell type, not only in our retrospective review from our institution with Dr Hernandez but also in work from the NCI with Lou Staudt and Wyndham looking at the ABC which looks like it’s driven by the NF-kappaB etc., that for some reason we see that lenalidomide actually has multiple mechanisms of action, including downregulation of NF-kappaB, anti-angiogenesis etc. It was very interesting to learn just from actually another meeting we were at recently, a few days ago, that the common denominator there may be a marker, cereblon, which is a protein that actually is pretty disseminated, not only in normal B-cells, in B-cell lymphomas, myeloma cells but other malignancies, but that somehow when you see it and you utilise treatment with lenalidomide it works on the ubiquitin protease system and it can be different for different B-cell malignancies. But what’s curious is that at least in the myeloma data, and we’re looking at lymphoma at this time, is that when you have a downregulation of this protein you actually start losing the effect of the actual immunomodulatory drug. So I think also the only other thing that was very exciting is the incorporation now of Revlimid with, say, up front R-CHOP. Two different studies presented at ASH have demonstrated what appears to be, at least with small numbers, that you can take the up front ABC patients which do worse than the GCB and be seen to bring them up to the same playing field, the same level, as the GCB. One other point is we always believe and we have data saying that maintenance rituximab is not effective in large cell lymphoma or aggressive lymphomas but there is some preliminary data now evolving that lenalidomide in patients who achieve a CR and have high risk, that actually they may be able to have better outcomes when they get post-induction therapy R-CHOP with lenalidomide.

JG: Now, Wyndham, your group of course have been long at the forefront of thinking about the importance of B-cell receptor signalling within some groups of diffuse large B-cell lymphomas. So clearly we’ll hear a lot more about some of the BCR pathways in other malignancies at the meeting tomorrow but your current views on the potential excitement of thinking about these types of agents and how they may help also to increase and improve our outcome of ABC diffuse large B-cell lymphoma in particular?

WW: ABC is  driven through a constitutive activation of NF-kappaB and there are two major pathways that lead to that. One is chronic active BCR signalling through the BCR receptor and the other one appears to be a co-operating pathway using the TLR pathway and MyD88. So a very important tyrosine kinase along the BCR signalling cascade is Bruton’s tyrosine kinase; there’s a very good drug that irreversibly inhibits that and there are a variety of different mutations downstream and upstream, all of which indicate the importance of BCR signalling as oncogenic events. So we did a clinical trial in relapsed refractory ABC and we found that as a single agent it has approximately a 41% overall response rate whereas in the germinal centre groups that doesn’t appear to have the chronic BCR signalling the response rate was only 5%. We’ve also found some very provocative relationships between where the various mutations are along the BCR cascade and the MyD88 TLR cascade and outcome vis-à-vis inhibiting Bruton tyrosine kinase. So these are all very interesting findings and they have now led to a large randomised study of R-CHOP plus or minus ibrutinib in untreated ABC large cells. I am very optimistic that this may be a trial that actually will show improvement and by that I mean increased cure rate of ABC large cells.

JG: So what do you think about the combination of lenalidomide, which looks like a different mechanism, potentially, of action of the NF-kappaB signalling pathway with that? So what do you think of that potential combination?

WW: I think that’s a very interesting one and Lou Staudt has actually shown that lenalidomide seems to affect more the MyD88 end. It does two things: it interferes with SpeB and shuts down IRF4 which is a stimulator of NF-kappaB. It also releases the brakes on interferon gamma. So it has a very different mechanism of cell kill and in the laboratory it’s highly synergistic with ibrutinib. So in co-operation with Pharmacyclics we’re actually starting a clinical trial where we’ll be using EPOCH-R plus lenalidomide and ibrutinib in relapsed refractory ABC large cell. We are hoping that with the potent synergy of these agents possibly shutting down these key oncogenic events that we actually may be able to cure some relapsed cases which hitherto are frankly the vast number of patients with relapsed ABC even with transplant are not cured.

JG: The other target of lenalidomide is the microenvironment so what do you think about instead of thinking about targeting the tumour cell but targeting the microenvironment? Targeting the microenvironment?

MC: I think that is an entire exciting field with respect to targeting the microenvironment but it’s very complex. I think we’re just gaining the infancy about understanding the complexity of the microenvironment. The whole idea of the different subtypes and work that you’ve done, John, with the synapse, I mean synapses in CLL, I think is very exciting but to try to understand all the different subtypes…

JG: So do I. Exciting signs but not ready for prime time.

MC: Exactly, for prime time, yes.

JG: So what we’ve been hearing today is that a lot of excitement from the first day of the meeting. Certainly our experts here are very excited by what we have heard and you’ll be able to join us tomorrow when we meet again to discuss day two from the International Workshop on NHL.