Meeting highlights from the 11th iwNHL 2013: Day 2

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Published: 15 Oct 2013
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Prof John Gribben, Dr Randy Gascoyne, Dr Wyndham Wilson, Dr Myron Czuczman and Prof Pfreundschuh

Day two of the International Workshop on Non-Hodgkin Lymphoma, held September 20th – 22nd  2013 in Dublin; meeting highlights by the Scientific Committee.

Professor John Gribben (Co-Chair of iwNHL 2013), Bart’s and Royal London School of Medicine, London, UK moderates the discussion between:

 - Dr Randy Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada

 - Dr Wyndham Wilson, National Cancer Institute, Bethesda, MD, USA

 - Dr Myron S. Czuczman (Chair), Roswell Park Cancer Institute, Buffalo, NY, USA

 - Professor Michael Pfreundschuh, University of Saarland, Homburg-Saar, Germany

Virally driven lymphomas such as those caused by EBV (Epstein–Barr virus), Novel Lymphoma Targets, and the question of chemotherapy free treatment for indolent lymphomas.

iwNHL 2013

Meeting highlights from the 11th iwNHL 2013: Day 2

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 day two on the International Workshop for non-Hodgkin’s lymphoma in the fair city of Dublin. We’re joined again by the scientific committee of the meeting where we’re going to be discussing what we heard that was new and exciting for us today and hopefully also for the other workshop participants. So we started off talking about virally driven lymphomas and, Wyndham, you chaired that session. We really focussed in the first half of the session on EBV which I think we already know and we thought we knew all about EBV but we’re hearing new things all the time. So why should people be interested and focussing and thinking about EBV in terms of the management of lymphoma?

WW: I think that EBV is a virus that actually infects across virtually all lymphoma types. You can find it in Hodgkin’s disease, you can find it in large cell, so I do think it’s an orphan disease and there could be specific strategies, some maybe immunological, that are more directed towards some of the EBV antigens. There needs to be a greater attempt to actually probe the actual tumour biopsies to see which ones are EBV positive and to begin to get a better understanding of how the EBV positive types of large cell and Hodgkin’s differ from their EBV negative counterparts. Only through doing that can we then begin to think about strategies and treating them possibly with different, more targeted, therapies.

JG: Francine Foss then talked about the very worst subtype of the T-cell lymphomas, ATLL, a field that probably most of us feel we’ve struggled with seeing any advance on recently. The difficulty of getting more aggressive therapies into these people and holding these people in remission and the difficulty of identifying donors in the subgroups of patients who develop those diseases have made this an extremely difficult issue. So we heard about some recent drugs coming out of studies in Japan, already approved there, so Michael, are you excited by anything you heard about in terms of incorporating those not just into ATLL but potentially into other types of T-cell lymphomas?

MP: Yes, I think it’s a step forward, even though not a big step, this antibody.

JG: It did look rather incremental.

MP: Yes, incremental. So I think there should be other developments, small molecules, targeting the pathways and the T-cell lymphoma also in the adult T-cell lymphoma. So far what I am missing is they have not directly attacked the HTL virus itself so there is probably still a lot to do. I myself have no experience at all because we have no Caribbeans, we have no Japanese patients in Germany so for me it’s totally a white map.

JG: That’s why I asked you about thinking about… that’s why I was asking you specifically about whether you saw any of those agents as being applicable to other types of T-cell lymphomas.

WW: I think I’d say probably the one pathway that needs to be looked at is the JAK-STAT.

JG: Right, studies going on at NCI right now, right?

WW: There are studies going on with that. Some people, because survivin gets up-regulated they have tried to target that. That’s probably more of a secondary phenomenon but we do know that early on in the biology of ATL that they are IL2 driven and so they are driven through the cytokine JAK-STAT pathway. So I do think that we do have some efforts there. Simply dialling up the chemotherapy in intensity has not really changed the natural history so I think we’ve got to move off that.

JG: We spent almost all of the rest of the day today talking about other novel more targeted therapies. So of the new agents that are in clinical trial development right now, Myron, which are the agents that most excite you, briefly?

MC: I think the antibody drug conjugates are very exciting with respect to their development with the success, at this point, of brentuximab vedotin which is a CD30 antibody drug conjugate with monomethyl auristatin E. With respect to linker technology it now can be applied to CD22, CD79B antibodies from Genentech. There is also a CD19 out there. I think it will be very exciting to see how this field develops because we are seeing activity and the ability to deliver very highly toxic therapy directly to the tumour cell with less non-specific toxicities.

JG: The thing that was striking me when I was hearing all the presentations today is that we’ve almost got more agents that are exciting that need to be developed now than we have the ability to have clinical trial patients enrolled into these studies. How are we going to be able to look systematically at all of these novel agents and start to think about incorporating what’s the best agent to be applying to which subgroup of patients? So Michael, how do you think about that?

MP: That’s a challenge and it becomes even more complicated because if one attractive target is identified you have several companies coming up with a drug so the patients are not only divided by the different targets we are aiming at, they are again divided into four or five by each company. I think we must develop new strategies how to integrate, not double and triple, the trials again. What’s a challenge is that we really, as investigators, are successful in gaining the support from different companies, especially when it comes to combining two new agents otherwise we’ll lose too much time and too many patients.

JG: Now that’s been a challenge and I know that was a challenge for you at NCI looking to get the lenalidomide ibrutinib study. I think it was a long time before when you were talking about wanting to do that study to when you started. Do you think you’re seeing any increased willingness in the pharmaceutical companies to start to work together and start to think about rational combinations or do you think we’re still stuck in an era of having to study one drug at a time, even when there are rational combinations?

WW: I think that’s a complicated question. I really want to go back to your previous question is how do we decide where we treat these, use these agents. What has been accompanying the development of these agents has been an increasing understanding of these being relevant oncogenic targets within the disease types. We can just go down the line: … seems to be they’re very much dysregulation of the PI3 kinase mTOR pathway so idelalisib and AK and mTOR inhibitors make sense. There appears to be tonic BCR signalling within the germinal centre which is down the PI3 kinase pathway so we would target that there. BCR signalling with NF-kappaB of ibrutinib down there. So I think we can just walk down the line and we can make very rational judgements about where we ought to be focussing these drugs. If we can then go to a company and say, ‘Listen, we have a combination which is likely to be highly synergistic based on mechanism,’ and work out with them or they work out the various IP issues so it’s a win-win for them, then I think that we will be able to engage companies. But if you just walk to them and empirically say, ‘Well I want to throw this and this together,’ without a true mechanistic underpinning you’re going to have trouble. Let me just take us all the way back to the FDA as well. The FDA has said that they will approve two drugs, of which neither is approved, if in fact the combination is highly effective clinically and there is a rational mechanistic basis for combining them. So I think the answer here is we need a rational mechanistic basis and we need to move beyond the ‘Let’s combine these in vitro and if they’re synergistic, even though we’ve no idea how they actually work, let’s throw it in.’ That is a bygone era, I think, and through more rational approaches we’re going to better with the FDA, we’ll do better with the companies collaborating.
JG: Lastly we heard, yet again, a debate on where does bendamustine-R fit in front line therapy. Argued here as a debate between … and Ton Hagenbeek. Do you think the debate settled any arguments between the views? I guess one thing that’s very clear is that irrespective of how flawed the data of any one individual trial might be, we’re faced with the issue that the uptake of the use of front line bendamustine rituximab for follicular lymphoma is already very high already in the US and now increasingly so, particularly in Germany, but now all throughout Europe we’re seeing increased rates. Has the argument already been won? Is it the case that we’ve accepted that it’s probably, BR, not an inferior therapy but is indeed less toxic?

MC: It appears that with the amount of rituximab bendamustine being utilised as up front therapy in the US, is clearly that it won, at least in the private sector, and a lot of people in the academic centres using it. I believe that people are using it because it’s easier to give, less of the toxicities associated with alopecia etc. We’re not convinced necessarily that we have all of the answers yet, however, we have to say of people’s utilisation, doctors’ utilisation, it has won but it doesn’t mean that it doesn’t change. Because with all these new things we’re talking about it may change very quickly. One in particular is the R-squared, the Revlimid rituximab trialled in follicular up front that will be pretty interesting.

JG: Now, I was struck by how often bendamustine and rituximab is being used as a backbone for some of the combination studies of more novel agents. So in many respects maybe it has already been adopted in. I’m also quite aware that the drug doesn’t have exclusivity in its use so it’s highly unlikely we’re going to see the sorts of trials that we’d all like to have seen to define this question ever being answered. Do you think it’s just the case that this is going to be accepted as a suitable chemotherapy backbone or do you believe that we are indeed moving towards chemotherapy free treatments for indolent lymphomas? I’ll take you one at a time, 30 second answer.

WW:: I don’t believe that the goal needs to be chemotherapy-free. I believe the goal needs to be effective therapy with minimal toxicity. It is a misnomer to say that drugs that are not cytotoxic don’t have toxicity as well. So I really do not like this idea that we move towards chemotherapy free because it doesn’t necessarily mean safer.

JG: OK. Michael?

MP: The same opinion. I think it’s a directive to say chemotherapy-free but what are we substituting it by? By non-cytotoxic drugs but these are new drugs and we don’t know the long term toxicities either of these drugs. So I would be cautious to just leave chemotherapy and go to combinations like rituximab and lenalidomide, the long-term toxicity of which we don’t know.

JG: Last word from you Myron.

MC: Yes, I believe that whether it’s fortunate or unfortunate that the backbone for a lot of the trials, including ibrutinib and idelalisib, includes a bendamustine rituximab backbone and it’s already incorporated so it can’t change. The one point I’d make is I also believe that we’re not going to throw chemotherapy away, that it has to still be utilised and in the future we’ll see how we can change it. I think that the non-chemotherapy trials are going to accrue much quicker because patients prefer them, that doesn’t necessarily mean that they’ll be better outcomes.

JG: So what you heard again is that on day two of the International Workshop for NHL we were just as excited as we were on day one. We heard lots of new information about novel agents and lots to think about as we go home and start to think about ways in which we can incorporate these into our management and think and plan for future clinical trials. So that’s it from Dublin and hopefully we’ll have similar webcasts from the twelfth annual iwNHL next year.