Expert overview of hot news in lymphoma from ASH 2012 (1/2)
JG: Professor John Gribben – Barts and The London Trust Cancer Centre, UK
MC: Professor Myron Czuczman – Roswell Park Cancer Institute, New York, USA
WB: Professor Wolfram Brugger - Villingen-Schwenningen, Germany
JG: Welcome to ecancer. We’re here this evening in Atlanta, Georgia at the American Society of Haematology and we’re here to discuss some of the advances we’ve heard in the treatment and the management of patients with indolent lymphoma. I’m joined by two eminent experts in the field to discuss some of the work that we’ve seen presented here: Myron Czuczman from Roswell Park and Wolfram Brugger. So obviously this is a very exciting time in terms of thinking about the ways that we’re treating these lymphomas. There are lots of highly active drugs that are appearing on the field so do you want to talk to me about what are the things that have excited you in terms of some of these newer agents that are appearing?
MC: I think, John, a lot of these things that we’ve been talking about recently are really coming more into fruition, we’re getting more data on these novel targeted therapies. Especially of interest is a lot of these are now oral medications and we may be seeing some major changes in our treatment paradigms in the not so distant future. Amongst those we’re getting updates more with lenalidomide in different combinations in indolent lymphomas but also with respect to the kinase inhibitors, the ibrutinib, the BTK inhibitors but also the GS1101, which is against the PI3K inhibitor. It’s quite amazing that a few years ago I don’t think we would have expected to see such a rapid transition, a rapid accumulation of data like we’re seeing in the last year or two.
JG: It’s exciting to see so many drugs together but it also raises a challenge in terms of clinical trial development that we’ve suddenly got so many agents together. Now what we’ve seen here is a lot of therapies either in combination or in use with antibodies, we’ll come on later on to talk about some with combinations. I’m quite sure that none of us really believe that single agents are the way that we’re going to be going ahead to do this but are you impressed by the activity that you’re seeing in the indolent lymphomas for these types of agents?
WB: I think we need the combinations because we have also seen already in these refractory relapsed patients that there are nice remissions however they are not that long lasting and not everybody responds to ibrutinib, for instance, and also to CAL-101. So I think we really need to go forward with combination treatment.
JG: There’s a lot of interest, I think probably the American patients are pushing for this almost more, these so-called chemo-free regimens, the idea that we’re going to be able to move away from conventional type chemotherapy approaches in towards these oral non-chemo drugs. Do you think it’s a realistic expectation that that’s something we’re going to see?
MC: It’s something that is often asked and I would have to tell you maybe as recent as five years ago I would have said it was unlikely. I have to tell you, I’ve reconsidered that the possibilities are there and one example would be the R2 protocol and Nathan Fowler from MD Anderson, his data is holding up with respect to very high complete remission rates with just the combination of lenalidomide and rituximab.
JG: So the R2 combination being Revlimid and rituximab?
MC: Revlimid and rituximab.
JG: It’s a nice moniker, the R2 regimen, nice and easy to remember.
MC: Exactly. And I think we have to prove things but that’s going to be done; right now there’s a large phase III trial looking at R2 versus R-dealer’s choice chemo which also includes R-bendamustine as one of the choices or R-CHOP or R-CVP. I think that in that large thousand patient trial which is accruing well, I think it will be very exciting to see if we’re going to at least have non-inferiority but with a lot less toxicity potentially and it could be changing how we’re treating patients. Now, whether we cure patients or not, I believe we still have to utilise our old and mix new into it but I’m not quite sure we’re ready to have a completely non-chemotherapy free world.
JG: So we’ve moved, or we’re moving, already beyond the single agents into the agents certainly with rituximab, which makes perfect sense. I don’t personally find it surprising that a lot of the chemotherapy combinations that are being used with these novel drugs are bendamustine, which of course you in Germany have a lot more experience of as a community of clinicians in using. I say that because I think it makes sense to believe that if you’re going to add together the new agents with chemotherapy then using the chemotherapy that potentially has less toxicity makes sense. So what are you thinking of the data looking at bendamustine in combination with some of these novel agents?
WB: I think they look really exciting and I think that’s the right way to go. Bendamustine is very well tolerated, we have used it for many, many years in Germany; we have used it in combination with rituximab but also in other trials with other combinations. So I think it’s a good partner also for the new drugs.
JG: We don’t have a standard of care of treating indolent lymphoma and you’re right, that disease at the moment that remains incurable and we don’t know whether any of these new agents in combination are going to potentially get us above that threshold of eventually seeing patients cured. But at the moment you think about that disease of thinking of sequences of therapies, are you having any sense yet as to what is the kind of sequence of how you might consider front line therapies and what agents may be used at relapse?
MC: There was one oral presentation yesterday that looked at the up-front therapy and this is before the data on bendamustine. It was actually very interesting, they looked at whether or not patients received up-front rituximab plus alkylating therapy, and consider R-CVP, Rituxan including an anthracycline based chemotherapy, R-CHOP, versus Rituxan with a purine analogue, fludarabine. They didn’t have bendamustine in that analysis but it was very fascinating that when they looked at the initial therapy and looked at following with additional treatment that it seemed like the rituximab with the anthracycline based therapy as initial therapy seemed to give an advantage for the longest progression free survival to patients. So there was a suggestion, and I apologise, I don’t remember the first author, that the initial therapy may be important with respect to outcomes, long term outcomes. Now that was in the era when we did not have the targeted agents, the whole game plan could change right now so I think one thing that behoves us as investigators and people that are major institutions is we need long-term follow-up on these patients. Unfortunately it actually becomes a problem for us because a number of trials are done, once a trial has finished, follow-up stops based with the company follow-up but I think it’s very important for us to learn is there an optimal sequence that we should be giving these agents where we’re going to decrease the potential of developing resistance or maybe cross-resistance, because a number of these agents are now in the B-cell receptor and downstream from the B-cell receptor? I don’t know if we have any clue as to what kind of resistance; should we be combining two of these together, sequencing them and is there an optimal first, second, third? It’s going to be very fascinating, it’s a lot of work for us; I call it job security – we’re going to be in business a long time.
WB: I agree.
JG: Obviously what we need are some of these agents approved then we believe that the interesting stuff can start because at the moment they’re all owned by different companies and there are no combinations. I guess at the moment one would be, of course, that Abbot and Genentech have combined to look at development of the Bcl-2 inhibitor plus GA101, far too new for us to present any real data at this meeting but for the most part these have not been combined. So it is going to be a challenge for the study groups to be looking at which of these agents to take forward, how you design the studies. Is that something your own study group are considering, of how we take the information from this meeting in terms of planning your next studies?
WB: I think we will have to have an investigators’ meeting after ASH to discuss all these recent publications and to discuss further trial designs. I think that’s critical.
MC: I think it’s also important, John, some people pooh-pooh it but I think a good pre-clinical type of evaluation of these agents in combination or alone but in combination on various, not just cell lines but primary samples, lymphoma samples from patients as well as an in vivo model. We need to study it there to give us at least a rational approach to what combinations will be optimal. They may not work, as we know sometimes they don’t but I think just randomly picking agents and mixing them together is actually just a waste of time in a number of cases.
WB: I agree.
JG: So, of course, there’s two things you see when you come to each successive meeting: you’re seeing further follow-up on the studies that are already there. And, on the one hand you’re right, you’ve already raised it, that you are seeing very encouraging single agent activity even in the relapsed setting but we’re also beginning to see relapses occurring. The other thing, of course, that alters in a lot of these types of therapies, we’re used to having rituximab maintenance for defined periods of time but these drugs are often being given until progression. So therefore there are a lot of patients around there now who are continuing on this long term. Do you think very long term continuous therapy is something that our healthcare system is going to be able to ultimately afford?
MC: Well our healthcare system is three different systems but the one in the US is going to be getting closer to Germany and England in the near future, I believe, but we don’t want to mix politics and medicine. But I believe you’re correct, I think that eventually limitations are going to hit where these very expensive agents cannot just be given until patients progress. However, I have my own personal feelings that if we’re treating patients that have life threatening diseases that they have as fits third line for large cell lymphoma and if I found an agent that’s working for a patient, I would be very hard pressed to stop that agent with concern that they’re going to progress, especially if they’re not in a complete remission, so in that situation. However, in indolent lymphoma cases or chronic lymphocytic leukaemia to give these patients that, say, are not end stage, that are suddenly responding, I think there is going to have to be a certain amount of limitation. Whether or not… well, we probably would need to have to test either short versus long exposure to these agents, but my biggest concern, even with rituximab but with any agent, any drug, is the development of a resistance. I think what is very important for any of us if we treat patients, and especially for the companies, with these agents until the patient progresses it’s critical that we obtain biopsies on these patients at the time of progression so that we can evaluate the patients’ tumours to understand what could be the mechanism for the resistance and try to limit it or sequence it with another agent that could counteract whatever mechanism is predominating.
JG: I think it’s true to say, though, as we also follow these patients longer term we’re looking to see whether there’s any evidence of cumulative toxicity from long-term use of these agents, and I certainly haven’t seen anything at the meeting that concerns me that as you remain on these agents long-term that the toxicity increases. In fact, it seems to be that the patients who tolerate the drug well are the ones who then continue to take it but I’m not seeing any evidence of relatively long-term toxicity.
WB: I agree.
MC: I think that the one that is actually the most amazing is ibrutinib and there are patients on for maybe a year or more. The thing that really amazes me most is that it really isn’t myelotoxic and a lot of the targeted agents we use still have some degree, at least, of myelosuppression.
JG: Would that not be an indication that it really is a very specific kinase inhibitor by its design and therefore isn’t hitting the myeloid lineage? I guess for me, I was expecting we might start to see some evidence of hypogammaglobulinemia and you would turn your patients into Bruton type patients; we’re not seeing that. I think some of the more mature data was in chronic lymphocytic leukaemia where John Bird presented that immunoglobulin levels were actually rising as the patients’ disease was under better control. The other thing was we were talking about indolent lymphomas but of course the indolent lymphomas are a term to cover a whole variety of diseases, the vast majority, of course, being follicular lymphoma. Are you seeing anything, any kind of signal to suggest that some subtypes are particularly attractive in some diseases or you think that in fact we could be moving away from having studies in indolent lymphomas and that these sorts of agents will mean that we can treat all malignancies together in trials? What’s your view of pure follicular studies versus incorporating other patients?
MC: At least with the initial evaluations they have to have a broad stroke and that it is interesting, it depends on the mechanism of action. For example, with a number of agents, if it’s the B-cell receptor that’s turned on, what’s interesting is that at least we’re not talking about the ABC phenotype which is driven by the B-cell receptor being turned on, there’s more of an effect with ibrutinib where these receptors… at least in ibrutinib the BTK inhibitor works in ABC versus primarily the GCB. But I would say to you that I think that’s what’s nice about some of these novel agents, they’re not restricted just to the follicular subtype. One in particular that we didn’t mention yet is the entire aspect of antibody drug conjugates and Genentech actually has two that have been presented and not just restricted. I’ve worked on the one, CD79B, which is actually part of the B-cell receptor, and CD22, they have another, both with the same drug that’s on, brentuximab vedotin, which is SGN35, the monomethyl auristatin E, a microtubular toxin. It’s the same drug but now you can use it on different antibodies with a good linker and we have had presentations at this meeting where we’re delivering now drugs directly to the cancer cell. I think that’s a great advance; whereas in the old days you would give the actual toxic drug goes through the whole system, a lot of non-specific toxicities, I call it to my patients a pizza delivery service to your cancer cell but it’s not pizza we’re delivering. So it’s actually very exciting that with the linkage via technology that we have that in the future we may be picking different antibodies with different drugs or toxins on it; we may get away from infusing drugs, free drugs, into the body at some point, entirely get away from it and just use different antibodies to direct our therapies to the tumour cell.
JG: The CD79 antibodies in particular raise the issue, of course, that you can start to have combinations of various drugs that all work through the single signalling pathway which is conceptually attractive except, of course, it’s also nice to believe that you should potentially be combining drugs that have different mechanisms of action.
JG: So, coming back to your point, it would then depend very much on how we understand mechanisms of resistance.