EHA 2015

Expert overview on the recent developments in mantle cell lymphoma

Professor Gordon McVie – ecancer and European Institute of Oncology, Milan, Italy
Professor Simon Rule – Derriford Hospital, Plymouth, UK

GM: Welcome to Vienna, the European Haematological Association. I’m Gordon McVie and I’m the editor of ecancer. We’ve been filming a number of key opinion leaders in the corridors for the last day and we’re also doing some expert to expert interviews and my expert today is Professor Simon Rule from Plymouth.

SR: Good afternoon.

GM: Thank you for joining us. Tell us about mantle cell lymphoma. Not everybody watching this programme will know much about mantle cell lymphoma and I suspect the bottom line is that if they don’t know very much they need to refer a patient with mantle cell lymphoma to a centre straight off. So what happens when they come to you? Given the EHA meeting abstracts, there are quite a few actually, there are over a dozen on mantle cell lymphoma, how are you going to manage things or recommend other people to manage mantle cell patients? Up front, first of all, new patients.

SR: The first thing to say is mantle cell lymphoma is a rare disease, about one per 100,000 population. So in the UK, for example, we’re talking 5-600 new patients a year. So it’s rare, incurable and, of the lymphomas, it’s an aggressive type. We’ve got fairly good front line therapies now, particularly combinations of chemotherapy and rituximab; rituximab has made a big difference in older patients. In younger patients we tend to be a bit more aggressive, different styles of chemotherapy consolidated with an autologous stem cell transplant. Rituximab maintenance now established in elderly patients and data, very recent data, showing that in the context of autologous stem cell transplant rituximab maintenance adds progression free survival benefit as well. So front line therapies fairly well established. When patients relapse, though, it then becomes a bit more difficult. Whatever you tend to use then from a conventional perspective your responses are less adequate, so not as complete, and usually shorter. The big revolution in mantle cell lymphoma over the last couple of years has been some novel drugs and principle amongst those the BTK inhibitors. They really have been transformational. The interesting thing now is how we’re going to incorporate these novel drugs into our frontline and subsequent therapies. So those trials are being run right now. There are other drugs, there are four drugs in the world that have a licence in mantle cell lymphoma so ibrutinib, which is the BTK inhibitor, is the most recent but also temsirolimus in Europe, which is probably the least effective of the agents, lenalidomide, and there’s quite a lot of data on lenalidomide at this meeting, and Velcade, bortezomib. All those drugs have activity. What’s interesting now is where we add these drugs in to conventional chemotherapy, do we use them instead of chemotherapy? A lot of questions really.
GM: So bortezomib is in front line in one or two combinations?

SR: It is. Velcade has activity in mantle cell lymphoma, clearly, 30-40% as a single agent. If you add it to chemotherapy you get an additional benefit; I’ve done that for quite a long time now. There’s a recent trial published this year showing that if you add Velcade into standard R-CHOP chemotherapy, well it’s not standard because you take the vincristine out, then you get a significant PFS advantage. So adding Velcade into front line is close to becoming established. In every trial that has added Velcade to an established regimen in mantle you’ve seen a benefit. So it adds something.

GM: This is pre-transplant?

SR: This is pre-transplant, this is predominantly in patients who are ineligible for transplant, the older patients.

GM: And the costs? I thought I saw an abstract here on the costs of those front line therapies, because they’re more expensive but they give a longer…

SR: They are more expensive. That’s the balance, isn’t it? You get more bang for your buck. We can have a discussion about costs and it applies to just about every disease, doesn’t it, because all new drugs are expensive but you get a benefit for it. I guess that’s what government regulators are there to decide, whether that’s acceptable or affordable or not.

GM: And patients who are not eligible or who can’t have a stem cell transplant, is that the same kind of approach up front.

SR: Yes, so that’s the majority of patients. The average age at presentation is late 60s, it may even be a bit later looking at UK data. For those patients if you’re very fit then having an autologous transplant is an option but for the majority you’re looking at pretty much standard R-CHOP type chemotherapy, what one would use for aggressive lymphomas. Bendamustine increasingly being used, particularly in Europe and North America and getting to be used more frequently in the UK as well, and those two are probably comparable as far as efficacy is concerned.

GM: So is that the setting where you’re going to put the new drugs coming out of the maintenance arms? Tell us about the maintenance arms first of all because it’s a nice trial that you’ve been involved with.

SR: SPRINT was comparing lenalidomide as a sort of single agent against investigator choice single agent. So you’re asking the question whether that, in a randomised setting, was better than what other single agent drugs we had available.

GM: And in resistant relapsing patients with mantle cell lymphoma.

SR: Heavily pre-treated patients and investigator choice which of the single agents you were going to use versus lenalidomide. It was a two to one randomisation, so more patients, two patients got lenalidomide to one patient getting investigator choice, and a clear benefit for the patients getting lenalidomide over any of the single agents that were used.

GM: There were five on offer?

SR: Yes, and whichever one you used there was a benefit.

GM: But the numbers in the five other might have been quite small because of the two to one randomisation.

SR: Of course. And that’s the criticism, you get into subgroup analyses. But overall there was a PFS benefit.

GM: The approach was, I think, quite novel and I liked that a lot. I think that the intention to treat shows that lenalidomide has definitely got an advantage. You’ve got an abstract on quality of life in that study?

SR: Yes, so I looked at quality of life in that very study and it showed that the quality of life wasn’t… well, it was pretty much the same, basically, in both arms and of course the lenalidomide patients were treated for much longer. So quality of life was maintained despite that. There was some suggestion that there were some elements of quality of life that were slightly better in the lenalidomide arm but it certainly didn’t disadvantage patients. That’s a concern sometimes when you need a continuous therapy that that might have an impact on quality of life in patients but that’s not the case with lenalidomide.

GM: And now the question of what you’re going to do with that, then. Are you going to put that into the up front with patients who are not fit for transplant or are you going to go straight in for the younger, fitter patients? What do you think we should be doing?

SR: Lenalidomide in combination, there are a number of combinations that have used that with other drugs. It’s quite difficult to combine lenalidomide with other drugs because it’s quite myelosuppressive. One of the troubles is that these drugs are very good but the BTK inhibitors are that much better, they’ve trumped them really. They’re twice as effective with fewer side effects. So the question is what are we going to do with ibrutinib? And there are other BTK inhibitors, I’ll talk about those this morning at the mantle cell session. Ibrutinib in the context of chronic lymphocytic leukaemia has just shown a massive benefit in a publication last week at ASCO.

GM: No contest there? No contest.

SR: No. And those trials have happened in mantle cell lymphoma as well. The big question is can we use that as part of front line therapy and we’ve got a trial, I’ve got a trial, that’s just about to open in the UK which is going to compare ibrutinib with rituximab versus standard chemotherapy. So that’s the only trial in the world that’s going to do a head to head comparison of chemo-free versus chemotherapy front line. So that will answer the question whether it’s better. Then the other issue is how do you sequence these things. I don’t think anybody believes we’re curing people with these new drugs and it is exactly how you sequence them. So you can certainly salvage anybody after lenalidomide with ibrutinib, that may not be the case the other way round, we don’t know. We don’t yet have enough experience with the new drugs when patients relapse because they do seem to set off some resistance mechanisms that might make subsequent treatments sometimes tricky. And it’s difficult in a rare disease, that’s the other thing, to do sufficient trials to actually answer the questions that you really want to know the answers to.

GM: But strategically there are some really strong national groups in this field, which is really a lesson for some of the other solid tumour disease groups. Also on the rarer tumours like mantle cell there is really good collaboration.

SR: This morning’s meeting was the European Mantle Cell Lymphoma Consortium, so there’s a good European collaboration there. Within that actually we’ve got a couple of trials running, so there’s the major trial running between the major groups and then I’ve got my front line study which we’re doing with the Nordic Lymphoma Group. There are enough patients to do that though, yes, you have to collaborate, you can’t do these trials without big national groups getting involved.

GM: So nobody is being cured at the end of the day so what are the targets? I’ve seen some stuff on PI3K downstream targets and SOX, CD19, where would you put your money? Or are you doing them all?

SR: There are lots of targets; the B-cell receptor pathway is clearly where the action is and there are lots of potential targets within that. PI3 kinase perhaps isn’t the answer for mantle cell lymphoma. These drugs are active in mantle cell but the duration of response when you use these drugs is really very short. That group of drugs discriminates itself for the more indolent forms of lymphoma. BTK clearly very active in mantle cell lymphoma. BCL-2 inhibitors possibly very active, well we know they’re active. So it’s going to be combinations is the answer. I’ve got a trial that’s going to open later this year that’s going to combine ibrutinib with a BCL-2 inhibitor with an antibody. Now, whether if you combine novel agents that all have distinct mechanisms of action as far as killing is concerned you then potentially deliver a cure we’ll see. If you follow a TB-type model then that’s what you have to do, you have to combine these things. So that’s the way things are going to go quite quickly and what’s interesting is the drug companies have lined themselves up; they have interest. There are basically three BTK inhibitors right now that are being evaluated seriously and all of those companies have PI3 kinase inhibitors and BCL-2 inhibitors and PD1. So you’re going to see a number of combinations over the next couple of years and we’ll see. Of course you never know when you combine novel agents whether you’re going to get unknown toxicity. Of course we’ve been bitten by that over the years in the lymphoma world but hopefully combinations will improve efficacy without that.

GM: And what about the whole CARs area, the chimeric antibodies? This is a quite seriously potentially difficult area but also some very exciting preliminary results.

SR: Yes, fascinating. I was at a meeting in Chicago a couple of weeks ago talking about CAR T-cells. Yes, I’m going to have to go back to my medical school days and relearn immunology because I think cancer now is all going to be about immunology, that’s the way these things are going. Fascinating how these things work but some quite frightening toxicity in patients; patients requiring elective ventilation is a bit of a concern but when they come out the other end you’re curing some really, really difficult diseases. So I think if you can get the toxicity right… The trouble is people don’t know what’s actually causing the anti-tumour effect so if you dampen down IL6, for example, you might lose the anti-tumour effect. Fascinating, absolutely fascinating. Nice to have a lot of potential drugs to play with.

GM: It certainly is, it’s a good time. Simon, thank you very much indeed, I really appreciate it. Thanks.