2011 ASH Annual Meeting, December 10-13, San Diego, USA
Indolent non-Hodgkin’s Lymphoma in 2011: a game changing year
Dr Mathias Rummel – University Hospital, Giessen, Germany
Professor John Gribben – Barts and The London Trust Cancer Centre, UK
Professor Gilles Salles – Universite Claude Bernard, Lyon, France
JG: Hi, I’m John Gribben from Barts Cancer Institute. We’re here in San Diego at the American Society of Haematology and I’m joined by two eminent experts in the field to talk about the changing face of indolent lymphoma in 2011. So, I’m here with Mathias Rummel from Giessen in Germany who leads the study group for indolent lymphoma, and Gilles Salles from Lyon who, of course, is very eminent in the GELA group leading the studies on indolent lymphoma. There are a number of new agents that are appearing for use, but of course we’re talking, really, today about where we see treatment going. You’ve been very prominent in the field of looking at the role of bendamustine in the treatment of indolent lymphoma, do you want to just tell us where we think we are now and the basis of the studies that you’ve performed with your group on where bendamustine sits, in your view, in the treatment of indolent lymphomas?
MR: So, we had the basis of a phase II study in which we evaluated the combination of bendamustine rituximab in the relapsed disease setting and this, fortunately, gave us the basis for a randomised phase III study to compare this regimen against the so-called first line standard of care which is, in most countries, CHOP plus rituximab. And the idea was to show that bendamustine rituximab has a better tolerability profile and a non-inferiority in terms of efficacy. In the end we found that the tolerability was indeed better with BR than compared with CHOP-R in acute toxicity but, to our surprise, bendamustine rituximab came out to be superior in terms of efficacy compared to CHOP plus rituximab. That, of course, is influencing general practice, at least in Germany and in some other countries I know, because it was always a debate if we need an anthracycline containing regimen for the front line treatment for patients with follicular lymphoma.
JG: And you’ve compared bendamustine to both CVP and to CHOP so, in other words, you’ve looked at the question of whether an anthracycline is able to overcome some of the benefits. And you saw bendamustine in your studies to be superior to both?
MR: Another study was done in which it was compared to both, this was a company driven study, in my study it was just a straightforward randomisation one-to-one between bendamustine rituximab and CHOP rituximab. So there are many studies out there showing that CHOP rituximab is indeed superior to CVP rituximab, we have confirmed it in some trials here, presented in the ASH meeting, and also in the subgroup analysis from GAUSS study was showing that CHOP-R plus maintenance in that study was superior to CVP rituximab. So, at least in my study we only did compare bendamustine rituximab against CHOP plus rituximab.
JG: So the concept of better tolerability with good efficacy would suggest that even if we don’t yet accept that bendamustine should be the treatment of choice for indolent lymphoma, and I think maybe that’s something we could discuss more, but there would appear to be subgroups of patients for whom it would be an attractive option. Now you’ve looked, in GELA, at some subgroups in particular using bendamustine.
GS: Yes, as you mentioned, the debate may not be closed. I think Dr Rummel ran a very interesting and provocative study and I think we would like to see those data published and to see also some confirmation of this data. But, as he mentioned, it’s very unlikely that it’s inferior so what we may have is maybe a long term effect on bone marrow given the mode of action of this drug. But because of the very good tolerability of the drug, we are actually running a study in patients over 60 or 65 with a very brief scheme of administration of bendamustine. These are patients with intermediate features, not the high tumour burden patients but still patients that you want to treat. Instead of using rituximab alone, which provides some good results for these patients, we are using two courses of bendamustine plus rituximab followed by some rituximab maintenance. I think the study has almost completed accrual so we hope to present the results in one or two years. We have also some evaluation with PET scan, which I think starts to be important in this field. So this may be a place where we can use short, efficient, very well tolerated treatment without having any thoughts about what will happen in 25 years.
JG: Sure. So among the other agents that are being explored, lenalidomide is a drug which, of course, has a major role in multiple myeloma which is now appearing in indolent lymphomas and in chronic lymphocytic leukaemia. Where do you think that drug sits now, and in particular the combination of lenalidomide plus rituximab, the so-called R-squared regimen is being explored in a number of settings? Where do you think that fits right now in your view?
MR: It was shown by first results from Nathan Fowler that the R-squared regimen is highly effective. This gives us the idea if we probably could avoid chemotherapy or could spare chemotherapy in the future, so maybe have a chemotherapy free, very effective first line regimen in the near future or in the far away future. However, as always, a phase II study is generating a hypothesis and it was really a very impressive result that here Nathan Fowler has presented, so there are two questions arising from that situation. First, if the R-squared really can have the same efficacy as the rituximab plus chemotherapy, and the other thing, what is the next hypothesis, is if we should add lenalidomide to existing chemo-immunotherapy, for example like bendamustine rituximab. So what I have learned so far, also from that ASH meeting, is that there is a little bit more toxicity if you add lenalidomide to bendamustine plus rituximab so I would say the really big question is if the revlimid and rituximab alone would compare, in terms of efficacy, good enough with rituximab plus chemotherapy.
GS: I think Mathias Rummel just said exactly the field and based on Nathan Fowler’s data which were scrutinised by many people, we are just launching an international study, both in Europe and also America and a couple of other countries which will be a randomised study comparing the R-squared regimen to any R-chemo, including R-CHOP, R-CVP or R-bendamustine. So this study is called RELEVANCE and will be open in many countries and the GELA group will be co-ordinating this study and I think we expect the first patient to be randomised next week. So we are looking forward, it’s a large study, 1,000 patients, and obviously will look early on to confirm the good tolerability of this regimen as well as its efficacy because this is in patients in need of cytotoxic therapy.
JG: I’m guessing that obviously in these diseases we have to think also of the quality of life rather than just the prolongation or even the response rates. Are you assessing aspects of quality of life in those studies?
GS: Yes, we do assess those aspects. We also will look carefully regarding the tolerability of this combination on the long term because Dr Fowler’s study was limited to a few months, six months, eventually a few patients for one year. Here we plan to use a longer period of the combination of the drug and this has to be carefully managed on the long term also.
JG: There has been concern with lenalidomide in multiple myeloma in use in high doses about potential long-term effects. How long is the lenalidomide treatment going to be in that study and do you view that in indolent lymphomas there may be any role for lenalidomide as a maintenance type approach rather than part of the initial induction?
MR: Yes, that’s very important. We heard last year at ASH that there was maybe a small excess of second primary malignancies in patients receiving lenalidomide in the context of alkylating agents after autologous transplant or in combination with melphalan. Here in the study we are running, we used lenalidomide and rituximab without alkylating agents so we are less worried but obviously we will monitor that. We have an induction phase of 20mg of lenalidomide plus rituximab, followed by a maintenance which at the present time is limited for one year of lenalidomide with two years of rituximab, as shown in the PRIMA study.
JG: Now, of course, the other agent widely used in multiple myeloma which has been explored in indolent lymphoma now is bortezomib. Now you’ve had some recent views on this published in JCO, so where do you think bortezomib with or without rituximab has a place, if any, in indolent lymphoma in 2011?
GS: I think that bortezomib is a very active drug in myeloma, it has also shown activity in mantle cell lymphoma and may have some promising activity in some subtypes of diffuse large B cell lymphoma. There have been a couple of trials, phase II trials, investigating the combination of bortezomib with either bendamustine rituximab or rituximab CVP. When you look carefully about these trials, the results, I think it’s hard to find strong evidence that you had an efficacy that is really worthwhile and it’s quite obvious that you add some toxicity. There was a randomised study comparing rituximab alone versus rituximab plus bortezomib which turned out to be positive at basically adding bortezomib to these patients for a couple of months, just added about 1½ months more in terms of progression survival. So maybe it’s active in some patients and we’ll hear more during this meeting, maybe it’s active in all the subsets of lymphoma and maybe other indolent than follicular lymphoma, but I figure that at the present time there are definitely higher priorities in the field in terms of new molecules to be developed in this field.
JG: You’re right, there are very exciting new molecules that are appearing and the concepts are moving away from chemotherapy, as we talked about with lenalidomide, onto things like the BCR receptor signalling molecules, means that potentially we are on the threshold of moving into a new era in treatment of indolent lymphomas. But how long do you think that is going to take before we really see changes in frontline therapy?
MR: That’s a good question because we need to wait for the usual accepted parameter which is the progression free survival, a very long time with the treatments we have available nowadays. So we really need some surrogate parameter in order to find out earlier than planned if an investigated treatment has any benefit. That is also a very great challenge for the future - to find a surrogate parameter which potentially could tell us which kind of treatment is the better one. If we need for progression free survival in the median, then we have to meet nowadays with a combination of chemo plus rituximab plus rituximab maintenance more than six, seven, eight years before we can find out the difference.
JG: And, of course, those combinations put particular stress on the economy at a time where we also have to think about this as a disease that still remains incurable and we have to be thinking about what becomes our second and our third line therapy. But unfortunately we don’t have time to discuss that today. So I’d like to thank you both for talking to us, to discuss what are the new approaches we’re having in indolent lymphoma in 2011 and to discuss some of the important topics that we are seeing discussed at ASH in 2011.