Mantle cell lymphoma current treatment practices

Prof Georg Hess – University Medical Center Mainz, Mainz, Germany
Prof Christian Buske – University of Ulm, Ulm, Germany
Prof Steven Le Gouill – University Hospital of Nantes, Nantes, France
Prof Eva Kimby – Karolinska Institute, Stockholm, Sweden

GH: Hello, my name is Georg Hess, I’m a haematologist based in Germany and actually I’m attending the Current Treatment Practice meeting in Brussels. With me in a discussion for the next minutes about mantle cell lymphoma are Eva Kimby from Sweden, Steven Le Gouill from France and Christian Buske from Germany as well. We would like to discuss certain aspects of current treatment with mantle cell lymphoma. The first question I have to my colleagues is what do you think is the current standard in patients which are younger and in a good shape? What do you think we should do in daily routine?

CB: I can start. So what we do in Germany and which I think is in line with the guidelines also on a European level, international level, is that we think that younger patients need in some way Ara-C, so rituximab chemotherapy which contains Ara-C. So what is quite usual in Germany is to give in an alternating way RDHAP and RCHOP and what we also think is that it’s important that in first remission these younger patients get an autologous stem cell transplantation. So this is what we do at the moment but, of course, there are new data, and I think Steven can comment on this, which also shed a light on the role of rituximab maintenance in this setting.

GH: Steven, you had a presentation at ASH last year, maybe you can comment for…

SLG: Yes, thank you, thank you for the invitation. Yes, we presented the results of the LIMA trial which is a phase III trial that had raised the question of the rituximab maintenance after autologous stem cell transplantation. Before the transplantation we used only high dose Ara-C, RDHAP regimen four courses and patients go to the transplant. So it’s very close on what Christian described but without the RCHOP, so no alternative, and only four courses of chemotherapy instead of six and then go to the transplant. I think it’s important to underline that in LIMA there is no TBI; in the German and French regimens in European mantle cell network trial we used TBI. So this one standard of care is RDHAP four courses then autologous stem cell transplantation with R-BEAM and then we have the question of course, as you know, of the maintenance, maybe we can go back later about the maintenance questions if needed, if you want us to.

GH: I think we could do it and jump in. Maintenance in the younger patients is something which has evolved in other lymphoma entities and we have seen the results in the elderly population and it’s an open question after high dose, does it benefit? I think you did an interim analysis which gives us a first clue.

SLG: Yes, the first interim analysis shows that rituximab maintenance can prolong PFS. Of course it’s only an interim analysis, we need the final one and it will be done for the next ASH, not this year, we will have to wait a little bit before to get the final answer. But it appears, based on this first analysis, that a rituximab maintenance, even after autologous stem cell transplantation, gives strong benefits to the patient.

GH: OK, so I think this will be important to learn, then, next year if this really holds true and what we have to do with that in the future. So just going back to you, what do you think about the TRIANGLE trial which is now the next generation in the younger population? What are the questions raised in this trial?

CB: The TRIANGLE trial actually addresses one very important question and this is whether by adding targeted therapy such as ibrutinib we can actually improve standard treatments in younger patients. So what we discussed before, we think that Ara-C is important in induction, we think that autologous stem cell transplantation is important in first remission in these younger patients, the question now is whether by adding ibrutinib as one component we can improve on this. So this trial actually tests whether by adding ibrutinib to the chemotherapy part and to the maintenance part whether we can improve the standard. One experimental arm is even more provocative, let’s say, because it tests whether we can even omit the autologous stem cell transplantation by adding ibrutinib. So it’s a large, randomised phase III trial, international trial, testing our standard versus the standard plus ibrutinib versus an arm where we omit high dose therapy autologous stem cell transplantation by adding ibrutinib. So it’s a very important trial which will show how good ibrutinib is in improving our standard today.

GH: So though we have achieved quite a good standard of care these two trials will help us to further improve on that. Very important, but the point is most of the patients are elderly and so we have to think about the treatment of more than 70% of the patients who are not able to tolerate. Eva, what do you think is the current standard for this elderly population with mantle cell lymphoma, not candidates for an intensive regimen?

EK: That is of course very important to say that you can’t get an autologous transplantation. So we have not a specific age limit but most patients above 65-70 they can’t tolerate autologous transplantation. So today we mostly use the bendamustine rituximab for these patients but we also, of course, as always we like to have patients in clinical trials. In the Nordic group we have had several trials for these elderly patients and we have one now starting. But still I think the BR now also with the trial which we hope to see results from next year, the SHINE trial, had the BR plus ibrutinib versus BR alone might be important for the elderly patients. But also going back to when we discussed the autologous transplantation, we also have had for many years in the Nordic group not any phase III but phase II trials. What we have also discussed there is the follow-up of the patients with MRD. Is it important to go for MRD after transplantation and try to handle patients who get an early relapse or have remaining cells after transplantation. That is still an open question.

GH: I think this is a question in all treatment lines, first line and second line, and the point is we have got these tools available, rituximab was the first one shown to be effective in the elderly and probably in the younger population, but one of the important points is now that the variety of novel agents came on the scene and has entered the arena in mantle cell lymphoma, which is probably a pretty good model disease for a lot of lymphomas as it rapidly shows this relapsing, remittent course. So maybe we should just spot on this a little bit about the current data of these novel agents; you both mentioned ibrutinib already. So maybe you can update what happened in the last year or so, what came out on ASH, I think there were data on ibrutinib and lenalidomide as far as I remember. Maybe Steven you can comment?

SLG: For sure ibrutinib is the most promising drug. We now use it more and more in clinics and we see the good result that we can have with an oral drug. So it’s a very important targeted therapy and we see now, as Eva mentioned, that it will probably move from relapse to up front. It takes years times but I think this should go pretty fast for a new drug. But what is also quite interesting is that is not one drug, there are a lot of other drugs. So you mentioned ASH last year, so we heard about Revlimid and we know that there is a new trial called the SPRING trial where we expect to see also very good results; a paper is probably submitted for publication so we will really see what is the result of Revlimid monotherapy. It’s interesting because it’s also an oral drug but response rates are lower than ibrutinib. You have good responders but in terms of percentage less patients respond to Revlimid. However, it’s also a solution for some patients and it’s another opportunity. All these other new agents like the BCL2 or BH3 mimetic drugs which looks very active in mantle cell lymphoma, you have the PI3 kinase inhibitors so there are a lot of different new drugs that are coming in mantle cell that it’s a huge challenge for all of us because we have to know how we can manage with all these new drugs. Should we use them alone, in combination, but with what? In combination with chemo or without chemo? There are a lot of questions that will come in the future but we already are in the future now and it’s very interesting to see all these different new trials that are starting right now. I hope that we will be able to find new guidelines in the future. The wrong part of that, because there is always a wrong part of something good, is that unfortunately we see that every single group is with a phase II or phase I and it’s very difficult to have a global overview of these landscapes. We have to work all together to build a new trial and we will be able to answer two questions that we really ask. I think it’s a huge challenge for all of us to be able to work together in this.

GH: I absolutely agree. We need a consortium and we have to put our data into databases that we really can learn from the trial the maximum because especially as in mantle cell there are so few patients out there and it’s important to do the right trials. But I would like just to pick up your thought. If colleagues ask us where to use or which situation to use the novel agents, it’s always the question should we re-go for a second line chemotherapy, should we use an allotransplant, when should we use a novel agent? What is your advice if this question is raised?

CB: That, of course, depends on the clinical history of the patient. So when we look at relapsed patients of course the first important point is what this patient got as first line therapy, how long was the remission of this therapy, is it an elderly patient?

GH: What is a good remission for you?

CB: A good remission but when a patient actually has a relapse within one year or whatever, so that’s an aggressive clinical course and this is, of course, a totally different situation than when a patient has a remission longer than two years. So these are all very important factors which have an impact on the choice of your salvage treatment. So despite all these new and exciting developments of course R-chemo is still a backbone, also in the salvage setting. So when a patient has a longer remission it’s absolutely wise to think about to use such a repeat even, the rituximab chemotherapy, or to use an alternate regimen. At least at the moment as these developments of targeted therapy are still quite fresh, many people would use these new targeting therapies more in later relapse and second relapse after a patient has got R-chemo in the salvage setting. So this might change the more data we get but this is the case. And of course, which actually comes a little bit back to your point, what is completely unknown is what is the right sequence of all these treatments. Is it better to give first R-chemo and then the targeted therapies? Is it better to give ibrutinib early on and then to salvage more conventionally? So these are all open questions. So the good thing is that we have a whole arsenal now of treatment options but we should not forget that R-chemo still is a very important treatment option. I don’t know how you see this.

EK: Of course, it’s the basis still and we have also long-term follow-up of our treatments. But the new drugs we don’t really know and what you say, the sequencing is very, very important.

SLG: There is also a lack of companion test and this is also a limitation on the use of these new agents. We anticipate that some patients will respond very well to these new drugs and they should probably not wait to receive these new drugs while other patients will not respond, will not be good responders. Then we see that we miss something there, to know who deserves to receive this agent rather than the other one. This is where we need to work a lot with the pharma company, with the colleagues, with the people in the lab to be able to stratify or to have new companion tests that will prevent the patient from the side effect of the new drug and select the one that will get 100% benefits of the drug. That’s a lot of work for the future too.

GH: I think there’s a statement which everybody would subscribe that we need competent biology understanding and we don’t know enough about that, the various subtypes of mantle cell lymphoma, to really choose the right drug for these patients. But maybe to pick this point, all these drugs have been approved now for single agents: ibrutinib, temsirolimus, bortezomib as combination partner and lenalidomide will be approved. Do you believe, therefore, that single agent will be the future or do you strongly believe in combination?

EK: Of course it’s interesting to know more about single agents because it might be, like you say, if you find a patient or have a pathway which really could be affected by that treatment that would be very interesting. Because if you also combine all these drugs you also could have a combination on the normal immune system and normal B cells so you can also have side effects and also we know about lots of side effects already now from the drugs. But everybody is looking for a good combination and I don’t know but what we discussed during today’s meeting was just to use easy things like p53 deletion or p53 mutation which we know these patients are not very good patients for chemotherapy. So we could also select patients, we could really look for biomarkers. But still I would like to have single agent and have them in a consecutive way of giving them instead of combining everything up front. But it is not easy.

CB: But the trend goes clearly to combinations and, of course…

EK: Yes, it does.

SLG: MCL is not CML it’s a completely different disease and it’s a very heterogeneous disease. I think I personally agree with your comment. I will be very surprised to be able to cure patients with a single agent because there is always a risk of selection of sub-clones. There is a strong instability in the chromosome and in the genome in mantle cell so it means that there are different pathways, NF kappa-B pathway, PI3 kinase pathway, oncogenes, BCL2, so we need to target all these things.

CB: Yes, and we have already data which we discussed also today showing that, for instance, when you add to lenalidomide rituximab you get a much better efficacy when you add rituximab to ibrutinib, it seems to be. It’s a smaller phase II study to improve the CR rates and there is a very important trial ongoing, the so-called SHINE trial which we also discussed, which tests actually bendamustine rituximab plus/minus ibrutinib. When this trial is positive it will be a very clear signal for perhaps a new standard of adding ibrutinib to rituximab chemotherapy.

SLG: And it will be very interesting to have tumour cell collection of these patients that will relapse because we will learn a lot from relapsed or refractory patients, probably much more than we will learn from the responders.

GH: Last year there was an abstract at ASH, you probably remember, where the patients in the SPARK trials who responded not very well or had no response were analysed and there were a lot of mutations shown to be within the BCR receptor pathway and then they conferred resistance more or less. This would be very interesting to follow in all these trials on the one hand, and the other one it could be an instrument for stratification. What do you think about a model like, let’s say you have a patient failing ibrutinib for example and you don’t take the drug off and then you do a molecular analysis and find a second or third pathway and then you selectively add a drug or another just to block that, it would be less than ideal. Could this be something we should embark on?

SLG: That would be great, I hope that we will be able to do these kinds of things very soon. We need also new tools to do these things. We see that the complexity of the disease with all these tumour cells escape the treatment but from the clinical perspective, and we are all clinicians here, sometimes we need a real easy to use in every day practice exam. It’s nice to have all these genomic analyses but when you’re at your desk in front of your patient you can’t use it so it’s very frustrating. We need these things but I agree that there will be a bright future if we can do these kinds of things.

GH: It’s leukaemic, we can use NGS, NanoString technology is much more available. These should work.

SLG: And they are much less treatment if I can say that, unfortunately.

GH: And it’s cheap now compared to treatment. Genome analysis is €1,000, treatment for a month is €10,000…

CB: But nevertheless I think it’s still research and it’s far away from being relevant for daily practice. We have Effimetrics technology for a long time and tried to personalise medicine based on gene arrays and so on and when you look at daily practice so it has actually not really changed our approach. What has changed our approach, perhaps, is our very simple surrogate markers such as Ki-67 or the MIPI, at least in part, let’s say, to get an idea. But even perhaps still not really to stratify treatment so we are lagging really behind.

GH: Still but we need to be prepared, I think. In ten years or so it has to be here and it’s good that everybody realises that we need to do so.

CB: I think so.

GH: It’s a very complicated situation. Eva.

EK: We need also to do re-biopsies when the patient has a relapse and also patients not responding well to first line treatment you should take a new biopsy. That is very important.

SLG: And it’s also important to think that it’s a lymph node disease and you have different compartments. You have the tumour cells, the circulating tumour cells are completely different from the ones which are in the lymph nodes so we have to learn also these biologic systems that makes this disease much more complex than some others.

GH: This is interesting to see that, for example, ibrutinib works better in the lymph node compartment than in the bone marrow compartment. We need to understand that, that’s very important.

CB: The microenvironment protects the tumour cells.

GH: Yes, probably, so a second drug.

CB: And there are probably two programmes which should always run in parallel to clinical trials, this is a biosampling programme and we need registries. So we need large pan-European registries to learn more about patients. I think these are very important complementary programmes to innovative clinical trials.

EK: But also in an individual patient you know if that patient had a good response or not and you can also earlier on change your attitude to a new type of treatment. That is a problem, of course, if you are in a clinical trial because then you have to go on until you fulfil some specified criteria.

SLG: I think a great challenge in the future is to be able to follow the patient at every time of the natural history of their disease. Diagnosis, first relapse, second relapse, and this is regardless of the clinical trials, it’s just in everyday practice what happens, what is the natural history of mantle cell lymphoma in real life.

GH: This is something we now started in the EMCL, we have this registry for relapsed mantle cell lymphoma and indolent mantle cell lymphoma where on a pan-European basis we will collect his data. We try to have a biosampling initiative as well so I think this could be something really helpful for everybody to bring in patients and really have this data available because it’s so rare, as everybody knows, we cannot create trials for every situation, it’s a big difficulty in mantle cell lymphoma.