ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago
Interview with Bruce Cheson (Lombardi Comprehensive Cancer Center, Washington DC, USA)
European influence in the ASH/ASCO symposium was interesting this year. A couple of things, the German Hodgkin’s group, which is incredible and keeps on with these wonderful trial, they’re talking about state-of-the-art and early Hodgkin’s disease being two ABVD followed by 20 grays of radiation. What’s your American comment on that?
Well, we are now at the position in Hodgkin’s disease where we’re trying to maintain efficacy and reduce toxicity. In the old days, everybody got six cycles of MOP, and then they received six cycles of ABVD or a similar regimen with a lot of radiation therapy. What we found out is patients are not dying from Hodgkin’s anymore, but they’re dying of the late complications of our therapy, particularly radiation. So, the German Hodgkin’s group, which is just a phenomenal organisation, has done wonderful trials for quite a number of years, initially under the leadership of Volker Diehl, and now Andrea Engert. This is another one of their very important studies. They did a study over 1,300 patients with early-stage favourable-risk disease, and they randomised them in a two by two design to two ABVD or four ABVD, and 30 versus 20 grays. With reasonably long follow-up, what they’ve shown is that the response rates were in the high 90% for the chemotherapy, etc., and the duration of response was comparable amongst the four groups. Now, we no longer have to give four cycles of therapy, we can give two cycles of therapy. We no longer have to give 30 gray, we can give 20 gray. That’s the new German standard. Now, the question is, can we even do less than that? There are studies now looking at a couple of cycles of chemotherapy without radiation, and it would be quite good if we could do that as well. Where Hodgkin’s research is going now, is to minimise therapy. One way of doing it is using PET scans. There are a number of risk-adapted studies ongoing. For example, in the US, for our low-stage, low-risk patients, we’re doing two cycles of ABVD, doing a PET scan, and if it is negative, just giving two more cycles and stopping there. No radiation. There are other groups that are doing two cycles, PET scan, and one more cycle if it’s negative. I believe the Germans are even doing one cycle, and if the PET’s negative, just doing one more cycle.
This is PET with FET and deoxyglucose?
FDG-PET. Your standard, nothing new, nothing novel. So, we’re getting down there. I don’t know why we ever chose six cycles of anything, but we’ve been stuck with it for decades and now we’re realising that six is probably too much.
But it does take some courage when you’ve got an effective treatment, to sort of get down. It’s like radical mastectomy versus segmentectomy or lumpectomy. You really need pioneers like you and Volker Diehl to do this kind of thing.
Well, Volker was quite a champion of this disease for many years. He was a good friend of mine and he’s done some amazing things for decades of his life. Now, to reduce the risk is very good for patients. A lot of these patients are young, they’re going to live for many years, and you don’t want them developing cardiac disease, pulmonary disease, secondary malignancies, etc. The other things happening are that the number of gray going down, but there’s a movement from involved field. First there were the mantles and the extended fields, now it’s moved down from involved field to involved nodal radiation. So, things are shrinking, and as long as the outcome remains the same and the long-term effects are reduced, we’ve really made progress.
And of course, the imaging is helping that too. The improvement in imaging like FDG-PET and so on is also good. Now, just say to me a few words about another German study. This is a German drug which is as old as me, almost. Bendamustine was around when I was a medical student in Edinburgh, and it’s now coming into front line with rituximab. Tell us about that.
Well, as you know, it was developed in Jena in the GDR back in the 60s. It was developed to be a cheap alternative to Cytoxan, cyclophosphamide, which was another German drug. Of course, now, it’s a very expensive alternative to cyclophosphamide, but it hid out there until the wall came down, and it never really moved much. Eventually it started going out and I went over to see the data about a decade ago when the German Cancer Congress was in Berlin. I got invited there and they showed me these data of single-agent bendamustine in a variety of diseases – follicular lymphoma, chronic lymphocytic leukaemia, multiple myeloma – and the old phrase is, if something looks too good to be true, it generally is. So, we had another congress in Lisbon and all the data were presented, and they really looked quite good. I introduced the German company Ribosepharm to the US company and they made the match and that started the US trials. In the meantime, Mathias Rummel, who is now in Giessen, Germany, did some work with bendamustine. He published a nice paper in JCO on bendamustine-rituximab in relapse disease. A variety of histologies – follicular, marginal zone, mantle cell - showed response rates of 90%. We said, you know, is that really true? So, we reproduced that study in the US, exactly the same and got the same results. Then, he did what was one of the most courageous studies. We’re talking about courage, like with the Hodgkin’s. There is this god, R-CHOP. You can’t beat it down. He said, I am so impressed with my R-bendamustine data that I’m going to compare it head-on with R-CHOP. He met with a fair amount of resistance even within his own country, but he has his own study group of lymphomas.
They did this study, and it accrued over 500 patients in follicular and lymphoplasmacytic and marginal zone and mantle cell – and most of the patients were follicular. It was a randomisation to R-bendamustine and R-CHOP, and the results were surprising to some and delightful to others in that in both arms, the response rate overall was over 90%, but the complete response rate was 10% higher in the R-bendamustine, 40% versus 30%. The progression-free survival was significantly longer with bendamustine-rituximab than it was with R-CHOP. Too early for any difference in survival, right now, the curves sit on top of each other, but importantly for the toxicity data, the R-bendamustine was associated with considerably less alopecia, neutropenia, infections, mucositis, and neuropathy, all the things that patients can do without. And the only thing on the converse, there were more rashes and infusional reactions associated with the bendamustine-rituximab. So, you’ve got a drug that has a higher CR rate, a longer progression-free survival, and is less toxic with over three years of follow-up now. It’s really poised to take over as the new front line therapy for follicular lymphoma, which is really great for patients. It’s really bad for clinical trialists, because now, all of these studies have been using bendamustine for a platform for the development of new agents. Bendamustine with and without this small molecule, with and without this new antibody, and now there’s a move to move bendamustine up front, and now, everyone will have had bendamustine. It’s going to be harder to find bendamustine-naïve patients. We suffered through this with rituximab in years past, when everybody in the relapse setting was studying rituximab. Then, people started using it upfront, and you couldn’t find rituximab-naïve patients anymore. But, be that as it may, we will survive that problem. We now have a new, exciting therapy for the front line treatment of follicular and other low-grade lymphomas, and it’s also being studied in large-cell lymphoma, where there is some very impressive early results in older patients, even older than you.
Response rates of over 80%, and as you know, a lot of older patients have co-morbidities. Cardiac disease, renal, liver disease, we never had anything that really worked to offer them in this condition. We couldn’t give them R-CHOP or CHOP or anything like that. Here, we have R-bendamustine, which is well-tolerated. The PK is not age-dependent. It doesn’t affect the heart. It’s not… it can be tolerated well with moderate renal insufficiency and mild-to-moderate hepatic insufficiency, so it’s a good drug for those patients in particular, but also for younger patients as well. In this trial, it didn’t matter what age group you were in. The difference was consistent amongst the young, older, and really old patients.