18th Congress of EHA

The future management of mantle cell lymphoma

Dr Simon Rule - Derriford Hospital, Plymouth, UK  interviewed by Dr Martin Dreyling - Ludwig Maximilians-University, Munich, Germany

Welcome to EHA 2013 in Stockholm. My name is Martin Dreyling, I am co-ordinator of the European Mantle Cell Lymphoma Network and I’m joined by my established colleague, Simon Rule who is, in fact, the first PI of a number of clinical trials in this specific field but also being a member of the European Mantle Cell Lymphoma Network. A lot of things are going on during this year’s EHA annual meeting, so Simon would you just try to summarise what are the standards of care currently in mantle cell lymphoma?

What EHA this year is showing, it’s giving us some updated information on some of the established drugs that we know about, lenalidomide particularly. Looking at some of the standard of care autografting and then looking at allografting in patients that have relapsed. Then there are the emerging drugs, particularly ibrutinib and I guess the question is, seeing the quality of the data with that drug particularly, how is that going to translate into how we’re going to be managing patients in the not too distant future. You have very much designed the standard of care through your European studies in the younger patients and the older patients. The question from me to you is when you see what’s here, lenalidomide and particularly the ibrutinib study, how do you think that’s going to factor in how we’re treating patients in the future?

That’s a good point. For example, for the time being in younger patients really dose intensification is the current standard, including high dose Ara-C. The question is how may we intermingle these new molecular approaches? I think this will be really the scope of the next study generation, to set that up in a multi-modal approach. So, when it comes to the monotherapy, maybe you would like to summarise the data currently available for lenalidomide in relapsed mantle cell?

There are two presentations here, one looking at the MERGE study, which is lenalidomide in patients who have failed Velcade, bortezomib. The response rate is about 30% and CR rates less than 10% but the patients that get a CR, that’s very durable. So the duration of response in those patients we don’t know. Then there’s the bigger collection of over 200 patients who were treated across the lymphoma studies that included lenalidomide. Virtually identical results – response rates around 30%, quite a bit of neutropenia – 40%, thrombocytopenia, so a drug not without its handling difficulties. I notice that the median dose received about 20mg, I think, 25mg probably a bit too much.

I just would like to pinpoint that because I think that’s very important. What about the dose and the duration of treatment? You have done by your own, also, in IT some academic trials. What is your flavour? What dose and schedule would you like to recommend?

25 has been the standard dose that has been applied across a range of studies. My impression is that’s a bit too much, particularly in heavily pre-treated patients. I think you might get better responses if slightly lower doses were used, maybe not at the beginning but certainly when you get into on-going treatment. I think it’s a good drug, the question is where do we use it?

Any idea? You had published some provocative data on the gender subject.

Yes, our impression is very much that female patients do better than male patients. That seems to be… I think I’m seeing that generally, in fact. And when you look at indolent patients it’s pretty much split 50-50 men to women, so there’s something about female patients seem to be slightly different the way they behave. I know when you devised the MIPI you didn’t find a sex difference or a gender difference. So maybe within the trials that you’ve done that’s not been borne out, maybe that’s something we need to look at again, maybe.

Probably you’re right in that way that now applying these molecular targeted approaches, gender and metabolism, whatever, may play a totally different role. For chemotherapy in general males always perform less well, that is what we know from all kinds of solid cancer but this is quite striking, the difference you have observed. So when it comes to your optimal scenario, when you would have the freedom, despite NICE, to treat every patient how you would like to where would you put in lenalidomide?

Well I’ve always believed it’s a maintenance drug. I mean it’s a drug that essentially is turning on your immune system, if you like. So to me that’s best used in a minimal residual disease setting. Rather than using it as a single agent to treat patients with relapsed disease, I would rather come in with it when you’ve got some degree of disease control in a maintenance setting. Now, of course, you’re exploring that in combination with rituximab and that’s going to be very interesting but to me that’s the place to use it. One of the questions for you, you’re quite right with young patients high dose Ara-C, autologous transplant, that’s very much the standard of care. The French data at this meeting looking at mini-allografts in patients that relapsed after autography, it’s a little bit disappointing, isn’t it? Where do you think allograft has a role? Do you think maybe in some of the high risk patients, the high risk MIPI patients there’s a…? Maybe we should be using it as part of up-front therapy, possibly?

I do absolutely agree, although having said that I think we on purpose in our network try to check to get some data on patients where you would like to go for allo. So the real high risk patient, either being identified by morphology, the blastoid, by Ki-67, the sub-proliferation or clinical features. And unfortunately so far we’re able to identify the results of allotransplant specifically in these kinds of patients. What we do know, also allo does perform worse than in the low risk patients. The impression we got is that you need a certain intensity of conditioning. So with dose reduced conditioning our results, also in prospective phase II trials, are a little bit sobering. So what I would foresee for the future is really that allotransplant will be not the final answer but we really have to work on the molecular pathogenesis on mantle cell. And that of course brings us to the B-cell receptor pathway, a very hot subject, not only in mantle cell lymphoma but in lymphoma in general. Would you like to comment on current available data, for example, on the BTK inhibitor, ibrutinib?

That’s being presented… well I’m presenting it on Sunday. That’s 111 patients now and patients have been on drug about fifteen months, as far as this presentation is concerned, 70% response rate. The astonishing thing with that drug is that irrespective of the clinical parameters of the patient – blastoid variant, bulky disease, resistant, whatever you choose to pick, they all respond the same way. So there isn’t one group of patients that do particularly badly or particularly well, across the spectrum everybody responds. These responses are durable and the quality of responses seems to be getting better with time. So the longer you stay on the drug the deeper those responses are. The astonishing thing about that trial is almost 50% of the patients are still on the drug now and there aren’t emerging side effects, it’s a very, very well-tolerated drug. Of course, the beauty of it is there’s very little haematological toxicity which opens it up to being combined with just about anything. That’s the challenge, I think, when you have a drug as good as that, do you use it instead of chemotherapy or do you use it together with chemotherapy? That’s a fundamental issue that we have to work out, don’t we? I suspect that there’s a role for both of those scenarios. Where do you see it being placed?

That’s a difficult question because, as you’re saying, when experts discuss the potential of all of these compounds targeting the B-cell receptor pathway, the discussion goes all over the field, in first line, relapsed, in very early stage and in whatever – maintenance, induction. So it’s just too good to be true but I can confirm that - the patients we’ve treated, we have seen striking results. So my idea is that I think we have to be aware, and you might comment on that, do we have any intros in that way that we have some insight into patients becoming resistant to this kind of disease? I would be in favour of going on for combinations, just to avoid any kind of secondary resistances but I wonder, you have treated a lot of patients in this study, any…?

I don’t think there are any clues about resistance pathways yet. It seems to be different to CAL-101 where you get a good response but it’s pretty short-lived. So these are very durable responses and we don’t yet understand the resistance mechanisms. There are bound to be mutations, just like with Gleevec, this is going to happen but we don’t know anything about it yet. I think the scenario as to where you might use this drug very much depends on the patient group you’re talking about. So the concept of a chemo-free regimen, which we’ve talked about with lenalidomide and antibodies, perhaps becomes even more likely with this drug. So for elderly patients where you want to spare them the toxicity of conventional chemotherapy, to me it could be used very early on in the disease, maybe even up-front, fairly quickly. In younger patients we’ve got a very good standard of care and, as you rightly say, if you can pick the bad patients, maybe adding it in there is a smart thing to do. I’m not sure about maintenance at the moment. The challenge is for… the results you’ve got in your elderly mantle cell studies were fantastic with your R-CHOP-R, the outcome for that group of patients was better than what any of us imagined, really. Where do you place ibrutinib there? The question is do you add it in there or if ibrutinib plus an antibody is as good as that, then that’s a good result, I guess. But that’s a difficult trial to do.

That’s a very important question – how to move on in elderly patients. I think it’s really, as you say, we’re not quite sure. In the study so far it was unlimited treatment, correct?

Yes.

So moving on to real life I think it would be an attractive approach to apply it for a limited time, let’s say in combination, whatever. We don’t know. But coming back to the present, what is your current standard of care in elderly patients? I know you have performed also some studies in this specific patient population.

Yes, the reality is I work in a third world country, unlike you. So what I can use and what I want to use are two different things. In the elderly patient then, the R-CHOP-R is reimbursed and that’s what people do. Increasingly I’m trying to use bendamustine, that’s quite difficult for me, it’s relatively easy for you I guess. And that’s a drug that has many attractions, not least the fact that the up-front study with ibrutinib is a BR combination so that seems to be, if you’re looking for combinations that you’re going to add new drugs to that’s probably going to be the backbone of choice, not just in mantle cell but also in CLL. So that’s what I tend to do. I’m not using much in the way of purine analogues, certainly not up front. FCR is good but you don’t want to be using it up front; certainly in a relapsed setting it’s a good treatment. And in the more elderly patients CVP works well, chlorambucil works well in combination with an antibody. So it depends very much on the fitness of the patient sitting in front of me as to what combination I use.  Then it’s about how you sequence those drugs.

So we talked about typical patients, younger patients, high risk patients, what about is there something like indolent mantle cell lymphoma? Do you perform watch and wait in your daily clinic?

I’ve not done that for a long time and, yes, it exists. The trouble with indolent is you can’t pick those patients; I don’t think the SOX11 story completely hangs together. So my personal philosophy is I treat mantle like follicular lymphoma, applying exactly the same treatment paradigm. So if they’re asymptomatic, haven’t got bulky disease etc., I’ll watch them. And you get some surprises. I’ve had patients untreated for ten years who present with a nodal disease, not just with a leukemic disease. The thing is, you can’t pick those and one of the challenges for us is how we’re going to isolate that group of patients, perhaps in a way to protect them from some of the more toxic therapies we do use. That’s something that we need to work on together.

I think that’s a very important point, that specifically in mantle cell lymphoma you do have the time to wait another three or six weeks and just see what’s going on. Is it a progressive disease or is it just somewhat stable disease where you have the freedom to further watch and wait? I do agree, we have some hints to identify these patients, mostly it’s the CLL kind of features, maybe splenomegaly. I oversee a couple of cases with features, only GI involvement or even eyelids or whatever. But we might really miss some of these patients if we treat them all right away. So in younger patients it’s still our standard of care, I have to say, whereas in elderly, as you were saying, we take the freedom to wait for another three to six weeks and to see what’s going on. I think we nicely have summarised what’s going on here at EHA, we received an update and will receive an update also from you and that’s on the new compounds, namely the new modulatory drugs, the B-cell receptor. We talked about the standard of care in young patients, in elderly patients, also the scenario of the watch and wait patients. Anything you would like to add?

There’s one drug here that just hints as another new potential blockbuster and that’s the BCL-2 antagonist, the ABT-199. So we’ve heard about this drug for a while in CLL, spectacular tumour lysis so that’s a side effect, whilst a difficult side effect it tells you that it’s doing something. So being presented here nine patients with mantle cell lymphoma, nine partial remissions with pretty modest toxicity. Another oral drug, another one. This is going to be a challenge for us because we’ve got three oral drugs there – we’ve got the CAL-101, ibrutinib and this drug all oral, all well tolerated, all looking for a place and we don’t have that many patients to do all these trials with all these combinations. So I think one of the challenges for us as people that design trials is how do we prioritise that and what combinations do we use and how are we going to do that?  It’s a tricky challenge I think.

This will be really a challenge. All of them obviously seem to be better than what we previously used, the question is which patient is prone to one of these candidate drugs. I think it will be very challenging and, anyway, it’s a luxurious problem now, we have more than now options for our patients.

It’s a nice problem to have.

Exactly, a luxurious problem. So I think we are very much looking forward to what’s going on during the next five years. I think we will have a major shift of treatment strategies and I think we will move on from, let’s say, effective but unspecific chemotherapy moving on to better tolerated targeted therapy.

I quite agree.

Thank you very much.

Thank you.