2010 American Society of Hematology Annual Meeting 3rd - 7th December
Interview with Prof Wyndham Wilson - National Cancer Institute, Maryland, USA
Key lymphoma research from ASH 2010
WW Wyndham Wilson
IV Doctor Wilson, obviously a lot going on in the lymphoma field – I wonder if you could try and summarise some of the key data that’s emerging, particularly in the large randomised clinical trials?
WW Sure. I think that there are really three trials that I think are looking at some newer questions, and I think looking at some older ones as well. In the plenary session there is a very important randomised study looking at advanced stage follicular lymphoma that are asymptomatic, and asking the question as to whether or not the use of Rituxan will change the time to therapy. And so the way the study is done is it’s a randomised study to watch and wait, versus induction with standard Rituxan therapy, versus induction with Rituxan therapy followed by maintenance.
I think the very interesting finding was that with the Rituxan therapy, with a long follow up, time to first therapy has yet to be reached. Whereas as in the watch and wait group time to first... medium time to requiring first therapy was a little over 30 months, which is standard over the last 25 years. So I think it’s the first study that has shown that Rituxan in advanced stage untreated, folks can actually delay the time to requiring therapy.
There are also two other studies that I think have addressed some questions that have been out there for some time. There is an ECOG study that has looked at the Stanford Five regimens and patients with untreated Hodgkin’s lymphoma were randomised between Stanford Five therapy and standard ABVD therapy, and with the ABVD arm many of them received radiation as well. What that study showed was that there was no difference in outcome, so I think that really raised the question as to whether or not the initial reports of the Stanford Five having a better outcome obviously didn’t hold up. Now that doesn’t mean that Stanford Five isn’t a very reasonable therapy because it is giving therapy over a much shorter period of time than ABVD is. The thing about Stanford Five is that radiation is an inner goal, a part of it.
And then finally, there was a study that is going to be reported by the GELA where they have taken younger under 60 patients with good prognosis, untreated large cell. They have looked at whether or not their ACVBP regimen that they have tested in younger folks for many, many years, whether or not that, when combined with Rituxan still has an improved outcome relative to RCHOP. And the answer is, yes; that it turns out that in younger folks that the use of R-ACVBP does have a better outcome, really raising the question as to whether or not for younger patients with large cell, whether or not we should be using RCHOP.
IV Very interesting. In terms of new and emerging therapies – I know it’s such a big meeting – but perhaps we could just summarise some of the interesting advances? For example, in T-cell lymphoma – perhaps you could talk about that?
WW I think we’re really in a very exciting time because there are many different targets, there are many different approaches coming out, and there is also many new driver pathways that are being identified as well. So I think it’s a very exciting time and I think there are a number of agents now that have shown some very interesting outcomes. In the area of T-cell lymphoma there is the HDAC inhibitor Romidepsin that was recently approved by the FDA for CTCL, and there is now a pivotal study of it in peripheral T-cell lymphoma where the response rates were around 25% to 30%. So there is very little in the way of proved agents in the peripheral T-cell lymphoma space so this agent has shown activity, and the duration of responses were relatively long.
I think even another very exciting advance is a monoclonal antibody directed against CCR4, and this has been tested in ATL, adult T-cell leukaemia lymphoma, where the outcomes have been relatively unchanged for many, many years. Overall, the response rate was over 50% and this also included patients with high risk disease, so called leukemic or lymphoma ATL.
IV So quite a dramatic response?
WW Yes, very much so.
IV Switching to Hodgkin’s lymphoma, how about some advances there?
WW So Hodgkin’s we also have a number of interesting agents; I think that we’re all very interested about the immunotoxin conjugate called SGN35. What this is, it’s a conjugate between the antibody and CD30 that is an activation antigen on the presence of most Hodgkin cells, which has been coupled with Auristatin, a very potent tubulin, a poison. And although we don’t know what the final, overall, formal response rate is what we do know is that 95% of patients on this study had at least some tumour shrinkage, and these were all relapse, refractory Hodgkin’s. So this is a very exciting finding and really raises the question as to whether or not an agent like this should be brought into front line trials relatively soon.
And then also there is a very interesting finding with a new HDAC inhibitor, panobinostat that hasn’t been FDA approved, but also was tested in relapse refractory Hodgkin’s disease, and had an overall response rate of 27%. So I think these are two very different agents, but two agents that I think have the potential, hopefully, in the future to improve the upfront outcome of Hodgkin’s.
IV Excellent. And then perhaps finally, and perhaps even more challenging, to try and summarise some of the emerging treatments in non-Hodgkin’s lymphoma?
WW Right. I think this is an area that has many, many agents; I am particularly interested in some of the Tyrosine kinases. Doctor Lou Stout who I work with, has shown that a number of these Tyrosine kinases play very important roles in the BCR signalling cascade that seems to be a driver pathway in the activated B-cell, large cell type. And so we ourselves are doing work with these, but there was one study that is being reported here, not specifically in large cell but across a variety of different non-Hodgkin’s.
It is of course an older drug, dasatinib, and this is a pretty broad TKI agent, but it does hit SARC, SARC family kinases including Bruten’s Tyrosine kinase, and I believe it has some activity against CYC, and these are in the BCR pathway that appears to be very important for the ABC sub type of large cell.. And in that phase two study, taking all types of lymphomas, the overall response rate was 32%. So I think that we’ve really seen a host of different drug classes coming forwards from TKIs to HDACs to immunotoxins to monoclonal antibodies that are all showing activity – so I think it’s a very exciting time and a good meeting for hearing about these.
IV Okay. Perhaps just one final question – we heard from Professor Bertram Coiffier who is doing a very important study, the R mini CHOP in the elderly. What sort of studies are going on in the United States to address the treatment of lymphoma, in particularly elderly patients?
WW I think that one of the differences between the studies here and Europe is that we’ve not been generally targeting specific groups in terms of older or younger; I think that it certainly makes sense in older folks to try to reduce toxicity. For example, in the GELA they have been using different regimens in the elderly because they’re ACVBP regimen simply was not tolerated - so I think, looking at a more abbreviated therapy in the elderly makes sense.
But one has to consider that if you look at the original GELA RCHOP study and we look at ten years out, our event free survival is sitting around 35% or thereabouts. So I think one needs to be very cautious in people over 60 to not withdraw therapy because you may end up having a worse outcome. But I do think that if you can identify a very good prognostic group I think it’s very well worth looking at whether or not shorter therapy in that group may do just as well as standard CYC cycles.
IV Very good; excellent. Thank you very much, Doctor Wilson, for your time. It’s very challenging to try and summarise all these studies and all the emerging therapies, but I think you covered it very nicely.
WW Thank you.
IV Thank you.