ASH 2013
New therapy aspects for myeloid chronic lymphoma
SR: Dr Simon Rule - Derriford Hospital, Plymouth, UK
MD: Prof Martin Dreyling, University Hospital Grosshadern, Munich, Germany
OH: Prof Olivier Hermine, Paris, France
SR: Welcome to ecancer.tv. My name is Simon Rule, I’m a haematologist from Plymouth and I’m joined by two distinguished friends and colleagues, Martin Dreyling from Munich and Olivier Hermine from Paris. We’re at the ASH meeting in New Orleans, which is particularly cold for a change, and we’re going to be discussing new aspects of therapies for mantle cell lymphoma that have been highlighted at this meeting. So perhaps I can start with Martin, what’s struck you at this meeting so far?
MD: I think there are two parts; it’s fair to say that it’s not one compound, the one ground-breaking news but I think there are two aspects. The one is concerning the standards of care also in mantle cell lymphoma; we do have a couple of bits and additional information at this meeting: what is the role of the different parts of the multi-modal approach. Secondly the scenery is broadening, specifically for the inhibitors targeting the B cell receptor pathway.
SR: And which of the ones, apart from ibrutinib, of course, which got a licence a couple of weeks ago, which are the ones that you think look the most promising?
MD: It’s hard to say so far but there is a new theme, at least for me at this year’s ASH, which is, in fact, that we now have growing information that the compounds shouldn’t be too specific. So, for example, in different kinds of lymphoma including mantle cell lymphoma we’ve seen that if you inhibit the delta isoform of a PI3K, for example, it might well be that alpha or beta pops up. So it might well be that less specific compounds might be more efficient in the long run.
OH: And probably I will add that it’s not the only pathway which is activated in mantle cell lymphoma; we know that the translocation (11;14) so I think we have to find what will be the best combination of inhibition will kill the cell [?? 1:53], not only ibrutinib or the other pathway but maybe the combination of them might improve the prognosis of this patient.
MD: That’s an important comment because mantle cell lymphoma is not CML, it’s not one genetic lesion so it won’t be a one hit kind of therapy but you have to combine it in an intelligent way to finally overcome the disease.
SR: What about this sort of drive to chemo-free regimens? There’s the R-squared data here for up-front mantle cell lymphoma which doesn’t look that fantastic to me. What do you think?
OH: Yes, me too. Revlimid plus rituximab might induce some kind of response but probably those patients would escape. Also, we want to push to chemo-free but chemo-free with R-squared is not so not toxic as we would think before. Also we have to learn about the long run, if the response that we see may maintain, I’m not sure, it’s like 80% response rate as we do see now with classical combination chemotherapy.
SR: It struck me that that lenalidomide-rituximab data was nowhere as good as when they put the lenalidomide together with bendamustine, the Nordic group. That’s a much more active regimen; it’s toxic but you use low doses.
MD: I think it’s important to reflect what kind of disease we’re talking about and mantle cell lymphoma traditionally was always aggressive for our US colleagues and, in fact, for our European colleagues by some acute classification it was more an indolent kind of disease. The reality is it’s somewhere in between but in the majority of cases it has to be approached like aggressive lymphoma in that regard, if you want to achieve long on-going remissions you really have to combine… I personally do believe that chemotherapy still remains the backbone of treatment, for the time being at least.
OH: Also we have to understand how this combination is working because Revlimid might work to induce IDCC with rituximab but also it can block angiogenesis because there is some abstract showing that mantle cell lymphoma may induce angiogenesis which may play a role in the proliferation of the tumour and also [?? 4:05] on the cells and may act in combination with chemo. So if we do not understand exactly how it is working maybe it’s not a good combination. Probably the synapse effect is not the main one in mantle cell lymphoma, probably, as well as the results are not so good as we may see for follicular lymphoma, for example.
SR: For me, we’re in a bit of a hiatus; we’ve got the ibrutinib which looks fantastic. The best results are still with chemotherapy, now that might incorporate some of these newer drugs but all the trials are just starting now, in a couple of years we’ll have a better feel for what might be a better way of treating these things. But right now I think chemotherapy remains the backbone.
MD: I do agree and there’s one important point – every one of us is enthusiastic about ibrutinib because it’s very well tolerated, it has achieved the highest response rate we’ve seen for monotherapy but it’s fair to say we’re still missing the long-term outcome on a broader range. So I do believe ibrutinib alone will be not a curative approach but we have to integrate it in our current therapeutic algorithm.
OH: Yes, probably with adding chemotherapy we will prevent the occurrence of resistant clones to this monotherapy. So it would be naïve to think that, like in CML, we can cure mantle cell lymphoma with only one pathway because it’s a multi-gene disease.
SR: One of the challenges is how, because we all design trials, how do you design trials with all these new drugs coming? There are so many potential combinations you haven’t got enough patients to do the studies. How are we going to decide what we’re going to do?
MD: This is a challenge and we are now in the situation, luckily, in relapsed mantle cell lymphoma that we almost have more compounds or possible combinations than patients. That brings back the comment of Olivier that we have to perform these pre-clinical assays to consider what makes sense, what is really very suggestive and then really pick the winner within a clinical trial.
OH: And also in first line therapy now we’ve worked as an EMC network for almost twelve years, or something like this, and we have defined some kind of standard therapy and then we have to build on what we’ve found which is the best treatment. Actually now it’s a combination of high dose chemotherapy with RCT and rituximab and autologous stem cell transplantation, now we have to challenge this best, to limit harm, to add something or remove something but we have to keep going on what we have done previously. It’s a way to limit because [?? 6:36] some kind of firework and we can do everything on every patient which is a big challenge.
SR: The other challenge is because these drugs are coming so quickly, designing trials that are light on their feet so you can adapt within the trail almost to incorporate these news drugs. It’s difficult to do.
OH: Yes, but probably by relaxing tradition it might be easier to do it, to pick the winner depending on the age of the patient and the [?? 7:00] and the time of relapse and so on. There are a lot of parameters that we can include and maybe biology which is also maybe important.
MD: I think you make an important comment which is the pick the winner design. Simon, you were also involved in the set-up of this idea to really… I think we have to… As you were saying, we have plenty of different approaches and really to test them as quick as possible so we have to screen them somehow. The one thing is the pre-clinical screening, of course, but then if we go into studies the pick the winner design, doing a couple of phase II trials, is really the way to go. Would you like to comment on that?
SR: Yes, I think we have to pick a standard design that you can then compare drug with drug. So you’ve got the same inclusion criteria, same exclusion criteria, same ways of monitoring patients.
OH: And the same prognosis factor that we have defined before.
SR: Exactly, so rather than having to do a randomised trial you can do the same phase II in a number of countries and then compare between them. That’s probably the design we’ve got to move to and whilst we’ve talked about that for a while we’re getting to the position now where that’s a reality because there are enough drugs out there where we could possibly do that. But maybe for the moment it’s on some kind of chemotherapy backbone but as the targeted therapies get better we could perhaps challenge the need for chemotherapy.
MD: In fact there is a very nice presentation at that meeting, really, that’s so far pre-clinical but really combining the most effective compounds so far, which is ibrutinib plus a BH3 only inhibitor. I’m very much looking forward to this presentation because this gives you some flavour how to combine these approaches in an intelligent way and we really have to find out which patients are specifically prone to treatment A, treatment B, treatment C, whatever.
SR: So what about younger people? I think in younger people still the treatment of choice is… well, we put the consensus document together, didn’t we, for the transplants, that it’s an ARA-C based regimen followed by an autologous transplant. Now, the age old question is TBI or not TBI and you’ve got a very interesting… well, the pair of you have got a very interesting abstract here about the role of TBI looking retrospectively at three studies.
OH: Yes, I can comment on it. TBI, because we know that the mantle cell line is very sensitive to radiotherapy so we wanted to push TBI and actually it’s the only protocol testing the stem cell transplantation where the one, the first one, with the multicell network, the first protocol in which they have shown that high dose chemotherapy plus TBI improve significantly the prognosis of these patients so with this idea to use TBI in the next generation protocol. But TBI is very difficult to use in all countries so only in France and Germany we use TBI and a similar protocol from the Nordic group and Hovern group, they didn’t use TBI but they used in the front line induction therapy with high dose RC. We could compare because now we have a good prognosis marker with [?? 9:59] markers, compare the database and actually we have shown that TBI may still be a beneficial treatment in patients in partial response. But the ones in complete response seem to not benefit from TBI and actually we did some retrospective studies from the EBMT and we show exactly the same results – patients with partial response may benefit from TBI and the ones in complete response don’t benefit from TBI. Actually now the goal of the elution therapy is to improve the CR rate and so probably it’s not so bad, don’t use any more TBI in patients in complete response.
SR: The way I interpreted it, correct me if I’m wrong, was that if you’ve got the induction right, and maybe that’s giving enough ARA-C, you don’t need the TBI.
OH: Exactly. Even the [?? 10:46] and the high dose chemotherapy.
SR: It might be even better, of course. But the TBI compensates for not a very good induction.
MD: Well, that is partially. So the final results will be presented at this meeting and it seems to be, as you were saying, that for the PR patients even with a high dose ARA-C you’re not completely compensating. You see the difference is diminished but it’s not compensated.
OH: And actually we discussed this point yesterday and maybe we should compare with the MCell1 protocol in which you use only CHOP and Bim and the German protocol, first with CHOP plus TBI, to see if the difference is maybe bigger with not a good induction chemotherapy.
SR: So what’s your take home message, then, if you’re a clinician treating somebody giving high dose ARA-C followed by a transplant? What should they try and do outside the context of the trial?
OH: Yes, OK, if they could reach complete response I think to do high dose chemotherapy is fine. If the patient is in partial response they should either try to put him in CR or do TBI in the conditioning regimen. That’s the take home message.
MD: Maybe I can toss in a comment on bendamustine because you might be aware our US colleagues are testing bendamustine in the younger patients with mantle cell lymphoma within a randomised trial and that was comparing the hyper-CVAD which is somewhat following the same theme as the European studies, versus bendamustine, both followed by autologous stem cell transplantation. Now if you do that I think it’s fair to say for high dose ARA-C we have observed the long-term benefit, even for overall survival whereas for bendamustine the long-term follow-up, at least concerning overall survival, is almost identical to CHOP. Really making the point that if you’re going for bendamustine in younger patients I think you still have to keep dose intensification and then moving on to autologous stem cell transplantation.
OH: And one question I might ask to you, Simon, it’s about high dose ARA-C because we know it’s a very good drug but it seems that when we use only high dose ARA-C, a very intensive dose of ARA-C, it’s not as good as a low dose [?? 12:52] dose of ARA-C in combination with [?? 12:54] platinum, every six weeks is not so bad and to do a very high dose of high dose ARA-C seems not so good. Can you comment on that?
SR: As you know, that’s what I do. We did the trial with the Nordic group and it was stopped after five patients because three didn’t respond, but they were very high risk. They were all high risk MIPI and what strikes me is if you’ve got a high Ki-67 that probably isn’t going to work very well. That was the case with those Nordic patients, I think it was just by chance they picked three particularly bad patients. Our experience is about twenty patients now with ARA-C dex rituximab and it’s all worked apart from one. Apart from one and we added Velcade and it worked. So in your standard [?? 13:38] patients it’s fine, it’s well tolerated; I think high risk you’ve probably got to do something slightly different. And whilst I’m not a big CHOP fan, it looks like that does benefit that group of patients. So I think we’ve got to be a little bit careful about the patients we’re treating but I think that ARA-C alone works quite nicely.
OH: Yes, that’s true for elderly patients. We do that sometimes; only I do the ARA-C and it’s fine.
SR: The other thing you can do, which is what I do in older patients, you can just have a flexible dosing schedule so you just lower and lower doses as the patients get older and that works nicely. That works nicely.
MD: So you trust in bortezomib; any comment on the role of bortezomib in mantle cell because it’s registered in the US, right?
SR: Yes, I like Velcade in combination. I think it’s a good drug in combination and the French data here is very compelling when using the Velcade in combination with bendamustine. Using it subcut, very little toxicity, very little toxicity in that study, but very active. I think it adds a lot. You know, if you add it to ARA-C it’s a very effective combination.
MD: I do believe and I think the common theme, let’s say, for the old new drugs which is essentially the proteasome inhibitors, the mTOR inhibitors as well, the IMiDs, that you have to combine it somewhat with a chemotherapy backbone. Then it works and we have shown some in vitro data seeing some over-additive effect between cytarabine plus bortezomib. So that is exactly… I would follow completely your line that it’s one of our preferred combinations.
OH: And actually that is the protocol in the relapsing patient in which it has the role of Velcade as a randomised way in the European Mantle Cell Network, well we will know the response from ARA-C in a few years.
SR: Finally, what about antibodies then? There are some retrospective German data looking at rituximab after auto-grafting. OK, it isn’t a proper randomised study but gives the feel that perhaps there might be something there. And then there’s your Zevalin data. Now what do you think about Zevalin because the Nordic group added that and it didn’t add anything to their trial?
MD: So when it comes first of all to rituximab, maintenance after autologous stem cell transplantation, there are a couple of suggestive results in phase II studies or retrospective data, again, also by our New York colleagues. On the other hand, we are eagerly waiting for the French trial, and you might comment on the study design of Lima to get the final readout. I think if your study confirms that rituximab maintenance is efficient, and clinically meaningful efficiency, after autologous stem cell transplantation, this will establish the new standard. For radioimmunotherapy I’m a little bit less enthusiastic. We have done something after conventional chemotherapy as an early consolidation; our Nordic colleagues did something in combination with conditioning before autologous stem cell transplantation, it’s fair to say it does achieve high response rates but these responses, in general, are not long term responses. So the jury is still out; my gut feeling would be that your French trial will prove a clear-cut superiority over rituximab maintenance which will then establish the new standard, but you might comment on that.
OH: Yes, I’m very surprised about the role of rituximab as a maintenance therapy for the elderly group of patients. The patients who reach complete response with R-CHOP followed by rituximab as a maintenance therapy do very well, 85% response rate and a very long PFS, even better than the ones who did receive stem cell transplantation in young patients. So I think to keep the pressure with antibodies in these patients once they have a low burden of tumour, it might be a very good option and that we have not to forget this kind of option because antibodies with a low burden of disease might be very good. We would see after stem cell transplantation in younger patients you have a lower tumour burden that we can get and we see if by doing maintenance therapy we prevent the relapse. Actually the pre-emptive treatment from the Nordic group shows that after stem cell transplantation we can prolong the clinical relapse by 3.9 years, which is very high. We have not to forget the role of immunotherapy in mantle cell lymphoma, maybe not the same setting as we used to do before but maybe as a maintenance therapy. Also probably there is a new antibody that we are not talking too much in mantle cell lymphoma because of the new drugs that are very efficient but maybe the bi-specific antibodies that have been developed first in mantle cell lymphoma and they might be good as a maintenance therapy too. I think it’s not the end of the day for immune therapy, maybe in maintenance therapy more than in induction therapy I should say.
SR: Good. Any other comments about the meeting as it’s going on?
MD: I think it’s a striking meeting. It’s really the place to be to get the news and this is a compelling time. You’re really seeing new developments of treatments also in mantle cell lymphoma so this is really changing the field now. Ibrutinib is already, let’s say, a somewhat established compound, this tells us how quickly the field is moving.
OH: I look back ten years ago when we were talking about mantle cell lymphoma, it is the worst B-cell lymphoma and all patients relapsing at three years, almost all dead at five years. Now they are almost surviving at five years and no relapse at three years so we changed totally the landscape of this disease and it’s become maybe a chronic disease. Now we have to wait to see the end of the story but for patients it’s very good.
SR: Well thank you very much and, from New Orleans, we’ll sign off.
