SR: Hello and welcome to ecancer.tv. Today we’re in San Francisco at ASH 2014 and my good friend, Professor Steven Le Gouill from Nantes, and I are going to discuss some of the highlights from ASH with respect to mantle cell lymphoma. So, Steve, talking about chemotherapy first, I guess, and modern ways of managing chemotherapy, your trial which you’re going to be presenting tomorrow looking at rituximab maintenance following a transplant, do you want to just give us a flavour of that?

SLG: Of course, yes. It’s called the LyMa trial and it addresses the question of rituximab maintenance and, as you mentioned, it’s after autologous stem cell transplantation. So now we’re talking about the setting of young patients because it has been shown that it works in the elderly and can enhance the overall survival but nothing is really known about the young patients. In the trial what we observed, and this is an interim analysis so we have to careful, it’s not a final one, but we observed that the rituximab maintenance can significantly enhance the PFS duration and EFS duration. So it’s rather very good results for an interim analysis. So I think it will be a very important point for the future to take into consideration that maintenance, even in the young patient setting, to be taken up to the patient.

SR: And it’s three years maintenance in your study, isn’t it?

SLG: Yes, it’s one injection every two months for a three year period, that’s correct. And the other point of the study is the induction treatment, I think that’s something we also have to mention because it’s the first time that we started treatment without R-CHOP, R-CHOP is the standard of care in lymphoma and in LyMa we used R-DHAP which is unusual. We showed that after four courses of R-DHAP we had at least the same rate of response as after alternative R-CHOP or DHAP. So it’s the other information that we get from the LyMa trial.

SR: And, as you know, I like doing that myself. I don’t use CHOP, I use high dose Ara-C. What about the platinum, though, because that can often cause toxicity? You often use oxaliplatin, I think, don’t you?

SLG: Yes or carboplatin. It was open for the centres could choose, take the choice that they want – cisplatin, oxaliplatin, carboplatin. I don’t know if it’s needed in the induction of the treatment, maybe you can do without it but I’m not so sure. I think it adds something and if carboplatin is better or oxaliplatin and so on, I really don’t know, but it’s important to avoid the toxicity of the cisplatin.

SR: I’m sure you’re right, I’m sure it adds something. The other thing this conference is doing is showing us more information in some large studies in the drugs that are licensed – ibrutinib, lenalidomide, Velcade. Now, from a Velcade perspective, again you’ve been involved in a trial using that in combination in elderly patients with quite good results, haven’t you? That’s the RVVD.

SLG: RiBVD. RiBVD.

SR: RiBVD, it’s easy for you to say.

SLG: Yes, they will be presented by Remy Gressin in the same session. It’s good to have Remy also in this session and he will show good results. It’s more designed for the elderly. What Remy will show is that this regimen is well-tolerated and the results are at least as good as R-CHOP. If you address the question of the elderly RiBVD was sub-cue Velcade, it’s good toxicity and a very good response at the molecular level. So it could be also an option for the elderly or even at relapse. I use it sometimes at relapse for the young ones, it’s a good option. Rituximab, bendamustine, Velcade, dexamethasone, only good things against mantle cell lymphoma.

SR: I agree. It is a good drug, Velcade, I like it a lot. The toxicity is the issue and I think sub-cue is one way to go. The other thing is how frequently you give it and you give it twice a week, I like it once a week. Talking about maintenance, there’s a SWOG study being presented here that’s got Velcade in the maintenance setting twice a week which doesn’t seem to be that toxic in that regimen. But whether that’s beneficial compared to rituximab, who knows? I suspect that trial won’t get done and rituximab is probably an easier drug to give. But maintenance is a key thing, I think, for older patients.

SLG: Yes, and we know that the NF-kappa B pathway plays a major role in mantle cell so Velcade, it works alone and it can be combined with other chemo. So I think it’s a good option. For the SWOG we need a phase III, as you know it’s only a phase II, it’s a historical comparison so it’s rather difficult to conclude that it should be used up front and I agree with you when you say that the comparison between Velcade maintenance versus rituximab maintenance, well this way will probably never be done. So it’s a shame but it’s the way it is.

SR: And the other drug I’ve liked over the years is lenalidomide. The SPRINT study is going to be presented for the first time, so this is oral lenalidomide against investigator choice single agent which owes significant benefit to lenalidomide in that design. Of course you could criticize the investigator choice arm, they’re all single agents which, I guess, none of us really do. But for me what that showed was the lenalidomide was exactly the same as every other trial we’ve seen with lenalidomide – response rate about 40%, duration of response 16 months, something like that. It’s absolutely consistent across all the trials. If only we could pick the patients that responded, then it would be easy. Because again, to me, that lends itself to maintenance. There is a trial going on, of course which will take a long time to read out but that’s quite a nice approach from a maintenance setting.

SLG: I agree. I think lenalidomide has a real role to play in this disease. It’s an oral drug, it’s easy to use and for the elderly patient that’s a real option. And, as you mentioned, in the maintenance it’s something easy to do and it works. The question is who responds, or who will respond to lenalidomide. In my experience, I don’t know yours, those who respond do it quite fast so if you don’t have an answer within the first two or three months after the start of the treatment I think there are no reasons to go on. I don’t know if you have also this experience?

SR: Yes, I absolutely agree, absolutely agree. Two cycles, if nothing has happened it’s not going to happen, that’s my experience. And the patients that tend to respond are women, that’s what we said in our paper in the British Journal of Haematology, I don’t know why. People that have a more indolent behaviour seem to respond a bit better. I know there are patients that do respond that have got blastoid variant but that’s less frequent in my experience.

SLG: Yes, I have an experience with blastoid variant and I was quite impressed by the answer. But it’s difficult, I think it’s something you have to try when you have already tried, unfortunately, all the other treatment options. It’s something that makes sense to try lenalidomide alone or in combination with rituximab, that’s the other option.

SR: Which brings us on to R-Squared and, I guess, the revolution that is likely to happen over the next few years is evolution of chemotherapy free regimens. Rituximab plus lenalidomide, Revlimid, R-Squared is clearly the first one and there’s some data at this meeting of R-Squared up front which looks very good.

SLG: Yes, yes, I was quite impressed but where we have this with R-Squared because it makes sense in follicular lymphoma. I was not so enthusiastic up front or at relapse for R-Squared in mantle cell but I have to change my mind, the results are interesting and much better than lenalidomide alone.

SR: Yes, so the CR rate is 52%, I think that’s what the abstract says, of course we have not seen the presentation yet. I was struck by the neutropenia though – there was 50% of patients getting neutropenic, so while it’s chemo-free it has chemotherapy type attributes which you just have to be aware of.

SLG: Right, I think chemo-free doesn’t mean side effect free.

SR: Exactly.

SLG: We have to learn how to deal with these new treatments and to be careful, I agree.

SR: And that just brings us on to ibrutinib, of course, and there’s more data at this meeting, more mature data. So I’m on a couple of abstracts looking at long-term results of the phase II study, the one that was published in the New England Journal of Medicine. Over two years median follow-up now and a quarter of the patients are still on drug at two years which is really very impressive. The thing that strikes me is the side effects associated with the drug, the infection, diarrhoea, fatigue, all fall away after six months. So the side effects become less of an issue after six months although bleeding remains constant; that’s always a slight issue with some patients, of course. And there’s also data on the SPARK study which is patients that have failed Velcade, single agent, again showing exactly the same data as the phase II. So it’s very consistent.

SLG: Yes, it is. And now that we get more and easy access to the drugs this is what we observe in real life but we have to learn how to use it or to manage these new molecules. But you are the one who has more experience with the BTK so I don’t have any particular opinion. I use it in clinic, we have now good access, at least in France, to these molecules. What I’m looking for is to know how you can mix it with something else because I think that it will probably not be the drug, the only drug, and we’ll probably have to mix or to combine it with the other option. I don’t know if you… it will be your thing. We have some information at this new session.

SR: So Michael Wang is showing combination with rituximab and what struck me there is the CR rate is 38%, or something, which is much higher than ibrutinib as a single agent, suggesting that rituximab does add something. There were always these concerns that rituximab might be antagonistic, clearly not the case in the clinic. As you know, we’re going to be running a UK study that’s going to be asking that up front versus R-chemo and then if that works as a backbone that we can bolt some of these newer drugs on to. I think that’s the way things are going to go.

SLG: Yes, I agree. I think this chemo-free trial that you mentioned is very interesting as probably the direction we want to go to in mantle cell lymphoma. We have to be careful and to have good selection of our patients because chemo-free, is it as active as chemotherapy? This is something that we will probably get from the future ASH, new information about this.

SR: Yes, you have to be a bit careful, don’t you, because chemotherapy does work.

SLG: Yes, right.

SR: So sometimes you’ve got to not throw that away for chemo-free because that sounds great. [??].

SLG: Right, I think so. But perhaps we should think the other way around – now first we start with R-chemo and use chemo-free at relapse. But what if we’re wrong? We should think about the other way, start with chemo-free but keep in mind that we’ll still need chemo. In the history of the patient one time you will need or he will require to receive chemo. Chemo-free is probably not the end of chemo, it’s still a mixture, how to combine it together, that will be very interesting.

SR: That’s absolutely right. And the other thing that is being presented is some mutational analysis in patients that don’t respond to ibrutinib or have a short response, showing some problems with NF-kappa B pathway, for example, pointing to how one might combine things in the future. I think as we get more information that’s going to help us rationally design how we put these things into combination which is clearly the way forward.

SLG: That brings us also to the question of the maintenance. As long as you get the pressure on the cells you may also select some sub-clones that will emerge as new tumour aggressive, more aggressive or not more aggressive. This is also something which is interesting with this targeted therapy – if they target something very precise those cells will probably find another way to escape to this target. These questions of resistance and clones and sub-clones are probably key things. Even to select which drug you want to use in everyday practice, because we also have to take in mind that it’s chemo-free but it’s not financial free.

SR: That’s right, financial toxicity is not insignificant. But then we have to think about MRD, don’t we, and if we’re going to put these rational combinations together, which are not going to be cheap, how do we stop them? I think as we get smarter at MRD monitoring perhaps that’s the way we’re going to design things in the future.

SLG: I think we have some smart MRD monitoring. The question is now how to use it in clinical practice. We know where is the frontier between the good level of response or not a good level of response but I think it’s probably the way that we can save some money is to monitor, do MRD monitoring, and then take the treatment on the [?? 12:14]. You get MRD positive then you receive the drug and which drug according to your sub-clones. But that’s not yet possible.

SR: So it’s an exciting time, isn’t it? If we’d sat here ten years ago we’d have been talking about whether anthracyclines work or not, pre-rituximab, and now we’ve got all of these drugs. The challenge is how we put the trials together and we monitor patients, stop.  Toxicity, real and financial, are not insignificant, we’ve got to be smart how we do things.

SLG: Yes, yes, I think so.

SR: So it’s an exciting time.

SLG: Yes, and a good reason to see each other next year.

SR: And on that note we will finish. Thank you very much.