ASH 2015
ASH 2015: Highlights in mantle cell lymphoma
Prof Simon Rule - Derriford Hospital, Plymouth, UK
Prof Steven Le Gouill - University Hospital of Nantes, Nantes, France
SR: Good morning and welcome to ASH 2015. We’re in Orlando at the current ASH meeting. My name is Simon Rule, I’m a haematologist in Plymouth, and joining me is my good friend Steve Le Gouill from Nantes in France. We’re going to be discussing what’s been seen in mantle cell lymphoma at this meeting. So I’m going to start with Steve who’s had a couple of presentations here. Obviously there’s a lot of buzz about new agents but we must remember that chemotherapy works very well for young patients and your LyMa trial clearly very important with the maintenance rituximab. So this meeting there has been some MRD data and some PET data which is interesting. Do you want to just summarise what you found?
SLG: Yes, we made two analyses based on the interim data that we showed last year at ASH. As you mentioned, one was about the MRD and we all know that in mantle cell lymphoma MRD can play a key role in the future as a prognostic marker. So Mary Callanan from Grenoble presented these first results about MRD in the LyMa trial and she nicely showed that the MRD status before the transplant is a very important prognostic marker, meaning that, of course, MRD positive patients do worse than those with MRD negativity status. We could show that 65% of the patients reached MRD negativity before the transplant. I think the other interesting question about this presentation was the role of the maintenance. As you know, there was randomisation after the transplant between rituximab maintenance or observation and what we show on this first analysis is that the outcome of the patients is better when they receive the rituximab maintenance regardless of their MRD status. So even if you’re MRD negative before transplant it looks like you take benefits to receive rituximab maintenance which hasn’t been shown before. So it could help the clinicians to take the decision about should I or not change treatment based on the MRD, even if it’s too soon to have MRD driving strategy.
SR: But that’s an interesting point, isn’t it? That implies that the MRD is not that useful at that point. Clearly later on it might be because you might want to do different things.
SLG: Yes, you’re right.
SR: So the timing, when is the optimum time to be looking at MRD?
SLG: Well, there are some different opinions about these things. Based on the French trial, the MRD status before transplant is the more important time point but there are other data about MRD after autologous stem cell and after treatment. But I think it doesn’t make too much sense to look at after transplant because if the patient is still MRD positive after transplant then, of course, it’s very difficult to change the treatment because you already finished the treatment. So mid-treatment analysis makes a lot of sense, I think.
SR: So do you think going forward you’ll do MRD analysis pre-transplant and maybe do something else to make them MRD negative before you transplant?
SLG: That could be an option in the future. It’s difficult to build such MRD driven protocol, at least in the design of a large trial it’s difficult to do so. But I think we have to really think about that of course.
SR: Yes, it’s clearly very predictive. Tell me about PET scanning then.
SLG: Well this is also a very interesting thing, I believe, because we all use PET scan everywhere in every lymphoma entity but if there is one lymphoma entity where we don’t have so much data this is really mantle cell.
SR: Yes, exactly.
SLG: Where there is no, as far as I know, large prospective trial. Then we analyse the outcome of the patient regarding the parameters of the PET scan. There are two things we ought to summarise what I presented yesterday. If you look at the parameter at time of diagnosis, so before any kind of transplant, the SUVmax volume seems to have a very important prognostic impact on PFS but also maybe in overall survival. We found a threshold of eleven; below eleven you do better than if you have more than eleven SUVmax value. It’s the first analysis, we need another cohort to confirm these things so we have to be careful. But this is the first time that we could demonstrate that SUVmax or PET scan could have an impact.
SR: So, as we discussed as we were walking here for this discussion, to me that looks just like a surrogate for Ki-67. We know proliferation is probably the most prognostic thing there is. The more proliferative, the higher SUVmax, you would imagine.
SLG: Yes, I agree.
SR: So, to me, that kind of makes sense. If that stands up the PET is going to be a far more useful way of discriminating that than Ki-67 which is hugely…
SLG: And much more easier. Much more, much easier.
SR: And much easier, hugely. Very variable, isn’t it?
SLG: It could be a surrogate marker but it will not be so easy to demonstrate because Ki-67 when you do the calculation you do it on the biopsy. You don’t know if the biopsy will be exactly the same that the PET scan analysis which is a whole body analysis.
SR: But that’s why the PET is better.
SLG: That is why the PET is better. But if we can’t demonstrate that there is a clear link I think it doesn’t mean that it’s not a surrogate marker. Now, it’s really clear…
SR: No, I accept that but it makes kind of sense that it would be.
SLG: It makes a lot of sense. It makes a lot of sense, of course, yes. And the second thing that we show, that we investigated, was the decrease of the SUVmax value between the start of treatment and end of induction, so before the transplant. Then we found a threshold of a delta SUV of 30%. Remember it’s 16 DLBCL but in mantle cell it looks like 30% could be the threshold if you look at the decrease of the SUVmax. But that’s preliminary; it’s interesting and we’ll have to confirm these things.
SR: So I guess going forward PET maybe, MRD maybe, are going to direct the way.
SLG: Yes, but PET maybe on overall survival, which will be important.
SR: Yes, maybe direct the way we do things. So what about therapeutic things that you’ve seen here?
SLG: Well, I’ve seen a very interesting talk this morning, very early, around seven in the morning but maybe you want to comment about it?
SR: Yes, it was early to be talking. So I presented the randomised data of temsirolimus against ibrutinib in relapsed refractory mantle cell lymphoma which showed a huge PFS benefit in the ibrutinib treated patients which, again, most of us expected that was going to be the case because none of us believe temsirolimus is a terribly effective drug in mantle cell. One of the surprising things was how good temsirolimus fared in this trial. Normally when you do a trial with these drugs they’re often not as good as the previous studies but the PFS was over 6 months in the temsirolimus arm, which is…
SLG: As compared to ibrutinib?
SR: 15.8, so miles difference.
SLG: Yes.
SR: But that 6.2 is equivalent to the Velcade, it’s better than lenalidomide. So the comparative arm fared well, so very impressive PFS. No overall survival benefit yet although the… it wasn’t powered on overall survival and there was crossover. But it looks like that might translate into overall survival with further follow-up. The most fascinating thing which actually isn’t in the presentation and isn’t in the publication which is out now…
SLG: Yes, I read about it.
SR: Is when we looked at the response by prior line of therapy the thing with ibrutinib is everybody’s happy giving ibrutinib wherever because you know it’s going to work. So whichever line of therapy you use the drug you get a response. But what we did is we looked at progression free survival by line of therapy and there’s a huge difference. If you use ibrutinib first relapse that PFS was a flat line at 65%. Now, it’s not going to be a flat line forever, clearly, but that was the first hint that whilst response rates are the same you get a much better PFS if you use it earlier. So that’s telling us, really, that’s a drug we should be using earlier in relapse.
SLG: First relapse you mean?
SR: First relapse, yes, and obviously that leads on to front line and, of course, we’ve got a study that’s just starting in the UK looking at front line. So, yes, that’s telling us this drug really is robust and we need to use it earlier on. The other thing that was again maybe a surprise because a lot of us have had experience with ibrutinib and when patients fail it’s often difficult to re-treat. In this trial, basically because the patients were treated earlier, you could rescue just as many patients with ibrutinib as you could with temsirolimus. So that gives us a bit more reassurance that using it early isn’t going to be detrimental.
SLG: What was the follow-up?
SR: The follow-up is twenty months so it’s pretty robust. The overall PFS is slightly better than previous ibrutinib studies, again probably reflecting the fact that we were treating patients earlier than we have done.
SLG: And what were the reasons for the choice of temsirolimus?
SR: Originally, of course, this was a European registration trial and they had to do a randomised study but the phase II was so good the regulators accepted it. So this is the confirmatory study.
SLG: I have a question because there were also trials of Velcade and Velcade has been FDA approved also; temsirolimus was only EMA approved. We already know about also Velcade trials today as a maintenance, do you want to put some comment about the Dutch trial?
SR: There were two trials, weren’t there? There was an American one which, I don’t know what you think but I found a little bit confusing. So it was a chemotherapy backbone…
SLG: Let’s say it was confusing, yes. Let’s say it this way.
SR: OK, so we both believe it was confusing. So it’s a chemotherapy backbone and then a choice of Velcade as maintenance or consolidation, so two different ways of giving Velcade. Of course, because you had no comparator you didn’t really know…
SLG: Yes, making a historical comparison.
SR: A historical comparator, so that doesn’t make any sense because historical comparators are always worse. So I really wasn’t sure what to make of that. But then thankfully our Dutch colleagues did the right trial and did a randomised trial of no maintenance versus maintenance which showed no benefit. So overall my take on that was Velcade in the maintenance setting doesn’t add anything.
SLG: But did you notice that only a few patients were randomised? As far as I remember they started the study with 150 patients and then it broke down to at least 30 patients in each arm. So it looks like the first part of the trial, the chemotherapy part with the autologous stem cell transplantation, was rather tough for the patients with a high dose of Ara-C, that very, very high dose of Ara-C.
SR: They have some quite tight parameters by which you’re allowed to start the Velcade. So if your counts are a bit low you weren’t entering it. And some patients didn’t want to go on trial, I think.
SLG: Yes, I think so.
SR: And the criticism that the Dutch people got at the podium was that the schema they used for maintenance, which was 1.3 once a week I think, once a fortnight, wasn’t standard. There is no standard so I thought that was…
SLG: Yes, it was IV.
SR: It was IV, of course, so sub-cut is what one would use now but it just didn’t seem to show anything, did it?
SLG: Yes. I think your presentation today was an important presentation for the mantle cell lymphoma world, the landscape, because you really demonstrated and confirmed also that ibrutinib at relapse provides a very long response as compared to temsirolimus, Velcade doesn’t show any benefits in maintenance. So it looks like ibrutinib is, as we all expect, a very important molecule in mantle cell.
SR: Yes, I think the big surprise was that analysis on PFS by line of therapy. That both surprised and reassured me. Of course, the other thing that’s been presented here which we’ll just touch on, one BTK inhibitor is good, obviously there are competitors.
SLG: Yes, this was a question I wanted to ask you – we have one BTK inhibitor but there are a lot of others now.
SR: There are and, like you, we’ve trialled other ones. At the meeting here there’s a Chinese BTK inhibitor, who are based in Beijing.
SLG: Sounds logic.
SR: It’s true. Which looks very similar to the other second generation, the Acerta compound and the ONO compound, so active, clearly active and well tolerated. It’s a good place, having a competitive landscape.
SLG: Yes, it’s good.
SR: Whether they’re any better than ibrutinib, they may have a slightly different side effect profile, maybe slightly less bruising and bleeding and cardiac toxicity. Although they’re only very early on so with longer exposure these things might be similar. But having more than one drug, if they can get them licensed, will inevitably push the prices down which will be good for patients because they’ll be able to get access to these drugs.
SLG: For everyone, yes. So ibrutinib monotherapy, you think, is the future?
SR: Who knows? I’m, as you know, a big fan of taking things away so instead of chemotherapy rather than continually add it to chemotherapy. So there are two different approaches there. I think particularly in elderly patients why introduce additional toxicity when you’ve got a drug that’s so good?
SLG: It’s also a way to prevent from the emergence of resistance or sub-clones. When you put the pressure on only one target you take the risk to see cells that are not dependent on this target take the lead and then to see a more aggressive disease. That’s theoretical, I’ve seen nothing about this at ASH.
SR: Of course.
SLG: We are just making speculation about these things, that maybe this combo with this new target, whatever we call it, chemo free or whatever, could make sense. I think so.
SR: For the audience, Steve and I have got a trial that is a combination of ibrutinib, ABT-199 and GA101.
Exploring, just as you were saying, trying different ways to kill the cells. I think in relapse that probably makes a lot of sense; up front, who knows? It’s patient group dependent, I guess, for elderly patients you want to maybe add as little as possible to ibrutinib, for younger patients you want to try and cure them so combinations make a lot of sense.
SLG: Yes, I think so. In mantle cell we really have a lot of new drugs to test but it’s important to run trials to be sure that what we observe is the reality and not something that we want to see. I think it’s important to have still this phase III, maybe phase II, because there are not so many patients. But this year at ASH I think we have the confirmation of the ibrutinib, even after not so many doubts. But if we make some speculation about next year, what will be for you what we should be waiting for for ASH 2016?
SR: Well, I think we’re going to have longer follow-up in the studies we’ve been discussing. We’re going to have the first combination data, I guess; we might see more of these novel agents. I think the trials you and I are involved with, maybe not next year, maybe the year after that. But for clinicians it’s a very exciting time because we’ve got a lot of tools now. Ten years ago we’re sitting here, we’re talking about anthracyclines yes or no or rituximab yes or no; now we’ve got all these other things.
SLG: Or chlorambucil.
SR: Or chlorambucil. But the other thing is we’ve got to be smart about how we do the trials, haven’t we? We can’t do massive trials that take seven, eight years to recruit because with all these drugs we’ve got to do quick, quick studies.
SLG: Yes, it’s unbelievable how quick things… or how fast things change.
SR: So we have to think of a different way of doing these things. It’s an exciting time for patients and if you go into trials today you have a possibility of getting some very exciting drugs.
SLG: I agree.
SR: OK, thank you very much. Next year we’ll be talking about combinations for sure.
