Expert overview of hot news in lymphoma from ASH 2012 (2/2)
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: One of the groups that has looked a little bit less attractive with some of these agents has been mantle cell lymphoma where certainly the response rates are high but the durations of response look shorter than we’re seeing in other things. So do you think we need a different approach for mantle cell lymphoma?
WB: I think at least we need combinations in this disease. I don’t think that we only can hit the BCR receptor just with ibrutinib or CAL-101, for instance.
JG: Anything that you’ve seen at the meeting in terms of looking like a real good way to be thinking logically about anything you’ve seen in mantle cell lymphoma that’s particularly impressed you?
WB: Yes, there were some good trials with DHAP, with Ara C containing treatments.
JG: Yes, the new old… yes, absolutely.
WB: The new old drugs.
WB: Yes, revisited. It’s not clear whether we really need cisplatinum in this context.
MC: That was one of the big questions, actually, one of the oral sessions. The question that was from the audience was very good, it’s that when you look at the HOVON where there was R-CHOP, I guess for three cycles, and then R-DHAP for three cycles, there was actually a presentation, I think it was HOVON, and they were updating the European MCL trial. But then there was also another trial, forget the R-CHOP, just use the DHAP or the three parts of that.
WB: DHAP, R-DHAP.
MC: And I believe it was four cycles and transplant the patient and then somebody said, “Do you really need the cisplatin?” because one of the main toxicities was renal insufficiency.
JG: I think what’s clear is that it’s the Ara C that’s important and the remaining question is whether or not platinum containing regimens really add above that.
MC: I think that we need to re-think the way that we’ve been taught. We need more data before we can change the way we teach our Fellows and our residents but the idea is that we’re at a point where the road is going to be diverging dramatically. What I mean by that is we’re going to be using the Rituxan hyper-CVAD plus or minus an auto transplant approach with a big hammer or we’re going to finesse it with a bendamustine-Rituxan based type of therapy which is one of the big trials. It’s an inter-group trial in the States, we’re going to be looking at that versus BR and transplant for younger patients. The idea is do we really need that, can we use bendamustine-Rituxan perhaps as our anchor and then add something, one of the BCRs is better and then post, without even a transplant, use other agents to mop up. I think it’s also clear minimal residual disease is critical but if you can clear the blood at least, either by very sensitive multicolour flow cytometry or PCR, the patients actually don’t relapse, you can actually diminish relapse and actually put them back in remission.
JG: Of course you’re talking here about either using high doses of old drugs followed by autologous transplant versus the approach of looking at oral non-toxic agents given long term.
JG: Obviously a real advance could be if you could identify up front who are those patients who are going to respond to one therapy. But it’s a large dichotomy between an oral agent with very little side effect versus high dose Ara C and a transplant.
MC: I think it’s somewhere in the middle. I think it’s going to be the bendamustine, which is not the high dose, it’s the actually very well tolerated approach and our oral regimens mixed in with that.
WB: I think it’s also important to have a treatment phase where you don’t take anything, nothing.
MC: A drug-free holiday.
WB: A drug-free holiday, yes. I think that’s also critical. At least in Germany we propose to perform a treatment, let’s say for six months, and then we will be off any kind of treatment. That’s the best quality of life for these patients. If they don’t take anything that’s probably important.
MC: I think there was some recent data that came out that patients, for example, that are on Gleevac or the tyrosine kinase inhibitors and they need it to sustain for their disease not to come back and they put a time release cap on, they found that those patients were not always taking a pill every day. It’s kind of interesting.
JG: You’d think people that knew that the drug was working extremely well, but even in that setting the compliance for the drug was remarkably low.
MC: That’s what’s going to be interesting with all these pills, people are going to be taking them long term.
JG: Because we think that they’re relatively toxic-free because they’re comparing it to the chemotherapy but I think if you’re taking these drugs every day without a holiday I think it wears people down.
MC: And they do have… some of them are associated with some degree of fatigue, GI upset, diarrhoea, maybe not major but day after day after day it can be issue.
JG: So quality of life is going to become an increasingly important component of looking at it and of course the best quality of life is when our patients achieve and are maintained in CR. What, of course, we’re seeing with a lot of these drugs is we’re getting very good responses and they’re durable but do you consider that getting to and eradicating minimal residual disease remains the goal of our therapy now or are we getting to a point where we’re going to be having people live with their disease rather than have it cured? Where do you see the field of indolent lymphoma going forward?
WB: I think that depends on the age of the patient; if it’s a very young patient you certainly would like to have a complete remission which is long-lasting. On the other hand, if you have a frail patient, an elderly patient you probably don’t necessarily need to eradicate the last cell. So that’s the spectrum.
JG: I’m kind of struck by the idea that we’ll soon be in an approach where younger people would be getting old-fashioned treatment and older patients are going to be getting the most modern cutting edge type of treatment approaches where we seem to be at the moment because a lot of the single agent activity is targeting that frailer patient that can’t withstand the high dose type therapy approach that we’re thinking about.
MC: Also John what you just said is that it is interesting, I think it’s also a philosophical question – can you ever cure a follicular lymphoma? We know that we can put patients into prolonged remission durations; I have some patients that when we originally did our R-CHOP trial that at now twelve years still have not relapsed.
WB: Without any treatment? Further treatment? No maintenance.
MC: No two year maintenance rituximab. So you know where my stand is on that, everybody should be getting all these drugs long term.
JG: Moving on.
MC: Well the philosophy is that if we really believe that we can cure and eradicate the last cell then I think that we need to actually approach that, be able to measure. But the problem is that we don’t have a way of targeting and measuring the lymphatic system to see that every single BCL2 positive cell has been eradicated. The other philosophy is that even if you eradicate the last possible cell, whatever allowed the follicular lymphoma to appear in the first place, to be created, the cells can actually then still transform, you’ll have a new follicular lymphoma develop. So I would love to say that in our lifetime we can eradicate and cure patients but I’m very comfortable thinking that patients can live into their nineties by just rotating non-resistant, non-cross resistant types of therapies for the rest of their lives.
JG: Now you raise here a very interesting issue, that is that with the sorts of progression free survivals that we’re seeing with many of the agents we already have, the idea that we’re going to be able to design trials to show advances in that using the novel agents require very, very long follow up and that’s clearly not the way in which these drugs are going towards getting their approval. So again we’re back to the issue; do you believe then that for younger patients a chemotherapy-based front line therapy approach with or without some of these more novel agents followed by the use of these novel agents at relapse and progression might be the way that we’re thinking about this disease going forward?
WB: Yes, that might be a good way, I agree.
MC: I think, John, it’s reasonable.
JG: Now I did see something from your group on a subgroup analysis of your on-going studies in Waldenström’s suggesting that, again, a benefit for bendamustine over… is it CHOP-R that’s the other arm in that study?
WB: No, in this NHL7 trial the backbone is bendamustine plus rituximab. It’s not randomised, it’s only randomised between maintenance versus no maintenance in those patients. We have seen, and this has confirmed the NHL1 data with bendamustine rituximab, that it’s very effective in Waldenström macroglobulinemia.
JG: I haven’t seen much data in many patients in Waldenström’s in some of the more novel agents, have you seen any in that?
MC: No, there has not been much and it’s probably because they’re not a very common histology. But I’m sure that the number of the Waldenström’s groups are already planning, if not already initiated, some of the trials. We just don’t have any data on it yet.
JG: Well, you raised it, of course, before. So the relevant study looking at the lenalidomide R2 combination versus chemotherapy is a joint Europe… the French study group are clearly going to actively accrue as well as the US led by Nathan Fowler’s people. And the Waldenström consortium is coming together, you talked about the mantle cell consortium, so to get the sorts of patients that we need to be able to do these studies, and get the answers we need in a very timely manner, does seem to involve, now, international co-operation.
JG: Do you believe that there is still a place for national study groups and that those study groups go in and out of these consortium as they see fit and fitting or are we really moving towards true international co-operation in these sorts of study design?
WB: I think that would be helpful, at least for the very tiny groups of patients with indolent lymphomas. Probably not with follicular lymphomas but with mantle cell lymphomas, for instance, you can see the European groups are very strong.
MC: I think in the United States we do need to have some kind of cohesive… We have inter-group studies, I don’t think I would dismantle necessarily the different study groups because I do think it serves as a basis where you can then…
JG: There’s an infrastructure already.
MC: There’s an infrastructure; if we would lose the infrastructure I think we’d be even worse. So I do think it’s important but right now there is a lot more interaction between the major study groups in the US, a number of studies are inter-group studies now.
WB: Look at the AML studies, for instance, they work together across the Atlantic and it works.
JG: I think it’s also important because, of course, a lot of studies at the moment have been led by the pharma companies having their product, looking towards development. I think moving it from the next step of having a drug approved into how we’re going to put it into combination really then is driven by the academic questions being asked by the study groups and that’s where their place will come in, to consolidate the findings that we’re seeing presented at this meeting. So anything else that you’ve seen at the meeting that has really excited you?
MC: I think we’ve pretty much covered it. I mean there are a lot of exciting things; there have been updates, as you stated, but the antibody drug conjugates and the kinase inhibitors, I think, are going to make a very major impact and we’re going to see updated studies and data in the next several years.
JG: So do you remain excited by what you’ve seen at this meeting? Do you think we’re continuing to make progress and that original excitement we felt a few years ago about ibrutinib and… I can’t even pronounce GS-1101’s new name.
MC: I practiced it but I have to say GS-1101.
WB: I still say CAL-101.
JG: We can’t call it CAL-101 anymore.
MC: You’re right – GS-1101.
JG: So there was huge excitement when these drugs first appeared and I’m feeling tangibly that people remain very excited by these types of agents coming forward and by the almost challenge that we have of having suddenly having had not very much, the only new drug we had was bendamustine which you’ve had for a long time. Suddenly we’ve got all these agents together and I think people feel tangibly excited by what you go to and that’s very clear when you go to the sessions where these drugs are being presented, the rooms are absolutely full to bursting with people trying to get in to hear what’s going on.
MC: And I think it’s also a very good advantage and it is actually a positive that patients themselves understand and they’re getting this knowledge, this information, to participate in clinical trials. The only way that we’re going to actually answer the questions sooner are patients participating in clinical trials. That’s important but I think that patients themselves, especially in the States, are actually looking for these studies to participate in for themselves.
JG: Yes, I’ve been having some interesting conversations with some of the investigators here that tell me that the cohorts that they have for these slots they can practically fill up from their waiting lists and they’re opening and closing the studies incredibly quickly.
MC: Very quickly. Never before, probably, as quick as this.
JG: So what you’re hearing from all of us is that we remain very excited by many of the things that we’re hearing at the American Society of Haematology meeting here, particularly in the field of indolent lymphomas, hearing updates on many of the older agents being now combined with some of the newer agents. A lot of these very exciting novel agents remaining moving towards approval; hearing lots of news about how they’re associated with low toxicity and ways in which patients themselves are very actively involved in trying to move forward the process. So I think we all look forward to the next meeting to see further follow up on the very exciting data that we’ve seen here.