17th Congress of EHA, Amsterdam, 14-17 June 2012

EHA 2012 advances in lymphoma; lenalidomide and beyond

Professor Gilles Salles – Université Claude Bernard,Lyon, France interviewed by Professor John Gribben – Barts & The London Trust Cancer Centre, UK


Hello, I’m John Gribben and I’m joined by my good friend Professor Gilles Salle from Lyon and we are here to discuss some of the advances that we are seeing here at this meeting on the field of lymphoma and in particular some of the interesting work that we are seeing in follicular lymphoma with some of the newer agents which are appearing. There’s been a great deal of interest, of course, on the role of the immune system in providing some kind of prognostic value in this disease and it’s kind of interesting to see some of the newer agents that have an immunomodularity effect coming through. So would you like to tell us about some of the things that you have seen of particular interest in that area at this meeting?

Well I think at this meeting we continue to see many trials that are evaluating different ways of handling follicular lymphoma patients with immunomodulary agents. And probably in the line with the description of the potentiation of the activity of monoclonal antibodies by the use of drugs of the family of IMiDs such as lenalidomide based on some experimental work, which actually your group also has carried on, showing that this family of drugs can increase the cell kill by rituximab when the cells are exposed to lenalidomide. There are a couple of data suggesting that the combination of lenalidomide plus rituximab may be particularly active in patients with follicular lymphoma and other indolent malignancies.

Sure, they’ve got a very catchy phrase, the “R-squared regimen”.

Yes.

So Revlimid plus rituximab; it’s a kind of nice catchy approach.

Exactly. Well I think this approach was developed first by investigators at the MD Anderson and Martin Fuller has presented over the last few years a couple of updates on his early trials clearly showing that this combination in untreated follicular lymphoma patients provided a very high response rate, 95-100%, with a complete response rate, a CR rate, which was in the range of 80-90% or even more, even in patients with some tumour bulk. So based on these results there were a couple of other studies that have been presented during this meeting. One which I think is particularly important is a clinical trial that was led by the CLGB which randomised patients between lenalidomide or R-squared, lenalidomide plus rituximab. This were patients at relapse and they were randomised to receive rituximab at the usual dose or the R-squared regimen with a dose of lenalidomide of 20mg per day, day 1 to 21 I think. And I think the results are interesting because they reproduce the usual result of lenalidomide, eventually even a little bit higher, about 30% response rate and only 13% of patients achieving a complete response. But with a combination of R-squared the response rate is 75% and 32% of the patients did achieve a complete response in this randomised trial.  So clearly that has established that the combination of both agents is more efficient than lenalidomide alone and is probably more efficient than rituximab alone because in relapsing patients we will expect probably around 50% of response and maybe 15-20% of CR, so I think this is quite an interesting study which shows us that we can continue to explore that.

It’s very interesting because it confirms in patients in a randomised clinical trial the pre-clinical data that we’ve had suggesting that this combination has a scientific rationale, so it’s nice to see a study designed from a clinical trial from an observation that comes from the laboratory. There is also other work now looking at this combination in addition to other agents.

Yes there is a report from the Mayo Clinic which evaluated the combination of lenalidomide plus a combination of rituximab, cyclophosphamide and dexamethasone, the so-called RCD regimen. So it’s R-squared CD or len-RCD; I don’t know how we should call it. I mean this is a bag of different patients, 28 patients, it’s early results, it could be tolerated, this combination, it is feasible. I think the response rate is quite high, in the range of 80%, but few complete responses so it’s difficult at this time. I think it is quite early results to know what to do with these results.

Sure. Now clearly what we want to be doing with these results is moving forwards and looking as to how this drug is going to fit into our algorithm of how we’re treating follicular lymphoma and I know that the GILA have some studies planned in this area, so where do you see this combination of drugs going?

Well I believe that based on the early data from the MD Anderson it is really worth investigating whether this combination, the R-squared combination, could be a chemo-free regimen that will be investigated and treat a follicular lymphoma patient in need of chemotherapy. So what we are doing is a clinical trial, a randomised clinical trial, at a large international base in the US, North America, Canada, several countries of Europe, eventually Australia, which is called RELEVANCE. And what RELEVANCE is addressing is randomisation between the standard regimen, rituximab and chemo followed by rituximab maintenance following the PRIMA scheme, the chemo regimen could be RCVP, R-CHOP or add bendamustine, which is an interesting regimen too, and this is compared to an R-squared regimen with a standard dose of lenalidomide of 20mg during the first six months and then a diminished dose to 10mg and two years of maintenance. So it’s really a standard chemo on R approach versus a chemo free approach, R-squared followed by R-squared maintenance. So the trial just opened, a few patients are recruiting in the US, the first patients were also recruited in France last month, so we hope to see this trial running for a couple of years, maybe not too long in answering this interesting question whether we can treat these patients without chemo.

It’s very interesting; I mean there are an increasing number of patients who are looking towards approaches that don’t involve classical chemotherapies with the side effect profiles that we see and there are a number of agents of course appearing here. So it’s again, I think, a very attractive proposition for patients to be able to consider that we would be able to move away from our standard chemotherapies and the poisons we’ve used in the past. So the results of these randomised trials will tell us how exactly this fits in. Planning ahead, if the trial goes the way you are expecting, where would you see this class of agents having their place? Do you think there’s the possibility that they will replace front line chemo-immunotherapy or do you see them more as a salvage? Or what’s the role, perhaps, of maintenance with these sorts of agents?

Well I think this is one trial, and really addressing the role of these kinds of chemo-free regimens in the front line setting replacing immune-chemotherapy with a maintenance of two years, so it’s basically the same range of maintenance that we have right now after our chemo. I believe that these are not the only agents that can be given overall and we know that there is a lot of excitement about new agents that target the BCR, the B-cell receptor signalling, such as the Bruton’s tyrosine kinase inhibitors, inhibitors of the PI3 kinase pathway, mTOR pathway. And I do think that we will have to play a little bit around to define which one of the regimens should be put in first line, for how long will be the patients treated, which one of the regimens will be kept for second line or salvage. So I think we will have a lot of work in the future years to really define probably a new landscape for these patients where eventually chemo will be reserved for patients failing these alternating therapies. At least that’s probably our hope.

So what we are seeing then is a great deal of excitement with new agents appearing and, clearly at this meeting, continued excitement about the use of lenalidomide as a new agent emerging with good activity in patients with follicular lymphoma. You are hearing that the community is moving towards us thinking about having chemotherapy-free approaches to treat our patients with follicular lymphoma and continue the trend that we’ve seen over the last few years of improving the outcome of our patients with follicular lymphoma and potentially also now thinking about decreasing the toxicity profile that we use as we are treating these patients so that we can keep patients alive for longer in a very good state of health. So we are moving towards an era where we are being able to extend potentially the life of our patients and decrease the toxicity profile. So with that I would like to thank Professor Gilles Salles for sharing his time with us today and get back to the meeting and hear all the other exciting work that’s going on.

Thank you John.