Key research presented at ASH 2010

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Published: 21 Feb 2011
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Prof George Canellos - Harvard Medical School, Boston, USA
Prof George Canellos talks about the key research that has emerged from the 2010 ASH meeting in Florida. One trial of note compared the Stanford V treatment regimen with ABVD for patients with advanced Hodgkin’s lymphoma and revealed that Stanford V was not superior to ABVD. Prof Canellos explains why this lack of superiority and the adverse effects associated with Stanford V’s obligate radiotherapy indicate that ABVD is a more attractive treatment option. A second trial which avoids the use of radiotherapy involved patients with primary mediastinal large B-cell lymphoma. This trial demonstrated that treating patients with an intensified chemotherapy regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) and ICE (ifosfamide, carboplatin and etoposide), whilst only irradiating patients when it was necessary was associated with an extremely high survival rate. Prof Canellos concludes by discussing two trials demonstrating the effectiveness of targeting CD30 protein cells with the antibody SGN-35 (brentuximab vedotin) and one looking at treating post-transplant relapsed or refractory Hodgkin lymphoma patients with the histone deacetylase inhibitor panobinostat (LBH-589).

2010 American Society of Hematology Annual Meeting 3rd - 7th December

Interview with Prof George Canellos - Harvard Medical School, Boston, USA

Key research presented at ASH 2010

Speaker key

 

IV               Interviewer

GC             George Canelos

 

 

 

 

IV               More now, from ecancerTV, with George Canelos: Harvard, Boston; George, you’ve been in haematologic malignancy for quite a while; we’ve been to a lot of ASH meetings like this one here in Orlando; but I’m interested to know what, from your point of view, are some of the hot topics. I know you’ve been to some of the Hodgkin’s disease topics; now, tell me, what’s your feeling about what’s happening here?

 

GC             Well, what’s happening is that the importance of prospective randomised trials to change from what is standard therapy to something new; before people leap to go to something new, I think the whole world depends on prospective randomised trials. Now, at this particular meeting, a regimen that has the name, Stanford V, which is really 12 weeks of chemotherapy modified dose, and then obligate radiotherapy to anything that was five centimetres or bigger, is… was compared to standard treatment, ABVD, with or without radiation; and it turned out to be not superior.

 

IV               Now, you’re talking about the abstract from Ranjana Advani looking at local bulky disease, and then there’s another one, Leo Gordon at Northwestern; what did you find out?

 

GC             Yes. It was the same study; she just peeled off the bulky stage twos; basically, the whole study is just divided into two papers, and basically, from my point of few, any regimen that has obligate radiotherapy is dangerous because Hodgkin’s disease is a disease of young people, and if you radiate them, then you’ve got to wait for 30 years before you’ll see the toxicities to the heart, to the second cancers, and all the radiation toxicity we’re trying to avoid; and so I think Stanford V went down for the count, as they say.

 

IV               Because Stanford V was intended as a more mild regimen.

 

GC             Oh, yes; and it had very interesting early results from Stanford; and then the Italians tried a randomised trial and showed it to be inferior; and… but the radiotherapy wasn’t exactly up to Stanford standards; then the British National Lymphoma investigation did a randomised trial, and they had better radiotherapy, and they showed it was equivalent, and published it. And the North Americans have gotten around to showing their data at this meeting, which confirms it even further. So basically, it’s a horse-race between the two, and for my money, if you don’t have to radiate somebody, just give them chemotherapy, you are, in a young person, sparing them the risks of… lifetime risks of radiation toxicity.

 

IV               How much, then, has therapy for Hodgkin’s disease improved, in your view?

 

GC             Well, since I got into the field, dramatically; from almost 10% survival to, now, way up in the 75% to 85%.

 

IV               That’s with ABVD, mainly.

 

GC             With… with MOP, ABVD, with better radiation; all of it; better staging; it’s a very curable disease; it’s very…

 

IV               Of course, there’s the B-COP regimen that Folker-Deal, who won a prize yesterday, as well…

 

GC             He did, yes; and it’s a more intensive regimen, and, again, appropriate for the circumstance where you need more intensive chemotherapy; like a very high-risk patient; but fortunately, more people who pitch in the door aren’t high-risk.

 

IV               So, looking at these studies, examining Stanford V; the bottom line message for doctors is that they shouldn’t use it any more, then; is that… are you saying that?

 

GC             It’s equivalent; and if they wish to use it they could do it; they’re not depriving the patient; but for my money I wouldn’t do it, because of the fact that they have to irradiate a lot of people; 75% of the patients in that study were irradiated; in the Stanford study originally it was 90% of the patients were irradiated, so, no, I wouldn’t use it.

 

IV               And you can now avoid radiation and avoid the long-term consequences in younger patients, especially.

 

GC             In most circumstances; in the patients with very bulky disease, who, with chemotherapy still can’t be rendered free of disease, the PET scan is still positive, those patients will require radiation; and I think what we’re getting better at, and there’ll be… there are probably enough posters and biological studies here that the CD68 immuno-histo chemistry study on the tumour, showing that… whether the CD68 is present, will predict that that patient will have a tougher time with localised therapy, usually just chemotherapy. It may be a way of identifying patients who will require either more intensive chemotherapy or radiation, than if their localised…

 

IV               And something of the same vein but a different disease; I know at the session that you’ve been at, Craig Moskovitz from Memorial Sloan-Kettering in New York, he had a very encouraging study on large-cell lymphoma; could you tell me what you heard there?

 

GC             Well, it’s an entity known as primary mediastinal large-cell lymphoma; it’s almost a separate entity amongst the… as compared to nodal large-cell lymphoma; and it’s a disease of young people; like Hodgkin’s, it has some genetic relationship to Hodgkin’s but it’s not Hodgkin’s; and what he showed was simply that if you intensify the chemotherapy, what he did was offer a retuxan CHOP every 14 days times four; and then he consolidated that with two cycles of a regimen known as ICE; Iphosimide Carboplatin Etopicide; and didn’t irradiate the patients; and they looked at their PET scans, and if they were negative they did not irradiate the patients; and they had a phenomenally good result with an 88% survival rate.

 

IV               It’s a cure rate, isn’t it? And this is young women.

 

GC             Yes; it’s a cure; these are young women, spared of radiation…

 

IV               They have a lot to gain.

 

GC             Absolutely. That was very interesting, because a lot of people… a lot of practitioners still irradiate these patients, and I think that… people ought to pay attention to this kind of data.

 

IV               So, this is the triumph of chemotherapy; you can get rid of the radiation.

 

GC             Speaking as a chemotherapist, it is the triumph of chemotherapy. But it is; it is.

 

IV               But now, let me dip in; let me try some of these on you, George, if I may; because there’s this agent called brentuximab, which I think you’ve also found quite interesting; SGN35, in refractory and relapse Hodgkin’s disease; a paper by Robert Chen, City of Hope; what came up there?

 

GC             Well, there are several SGN studies around, but one was published in the New England Journal; there is a poster; I think there’s this presentation; well, what it is, is an immunotoxin, it’s an antibody directed against a marker on the malignant cell of Hodgkin’s disease called CD30; and it’s linked to a tubulin poison called auristatin; and it binds to the tumour cell; it’s taken into the tumour cell, and this auristatin with it chews up the tumour cell in some way – probably destroys the tubulin - and it’s pretty free of toxicity.

 

IV               Now, immunotoxins have always been attractive, because of their targeted ability; carrying…

 

GC             It is very much targeted therapy, yes.

 

IV               … a guided missile, as it were.

 

GC             Well, yes.

 

IV               But what did Robert Chen actually manage to do? What is he reporting here in this…?

 

GC             Well, he’s reported, and all of the reports are, that this is active to the order of up to 80% of the patients who obtain some benefit; now, most of these…

 

IV               That’s in refractory Hodgkin’s disease.

 

GC             Right; these are mostly end-of-the-rope type patients; and so something that is non-toxic, especially to the bone marrow, really - it may be toxic to nerves because of the tubulin poison - but it’s going to be combinable with chemotherapy.

 

IV               And there’s another paper on the same agent, SGN35, from Andrei Shustov with Fred Hutchinson; and that’s in anaplastic large-cell lymphoma; what’s the story there?

 

GC             Well, that’s a large T-cell lymphoma that also has CD30 on its surface; it’s a rich-CD30 tumour, and you would expect – and it does – bind, and it’s even more effective in that disease than it is in failed Hodgkin’s disease; it’s kind of interesting.

 

IV               But we’ve got news, also, finally, let me ask you about this one; an oral agent, panobinostat; Anna Sereda from Barcelona was talking about Hodgkin’s disease…

 

GC             That’s one of a big family of drugs called histone deacetylase inhibitors.

 

IV               And the hope there is what?

 

GC             Well, the hope is that it’ll provide some anti-tumour activity; and she showed that about 30% of the patients with failed Hodgkin’s disease could get a remission – albeit temporary – with this histone deacetylase inhibitor. Now there are a host of such drugs coming along, and one may be better than the other. There’s one, romidepsin, which has been approved for T-cell lymphomas; it’s on the market now, for example; and I think that’s a whole field that’s going to evolve, and hopefully better drugs will be found. Now, the histone deacetylase inhibitors prevent deacetylasing of the histones, and that allows for the enzymes, and genes in enzymes, that facilitate the death of a cell; apoptosis of a cell; and they may have… or they will have a role; whether you can combine them with chemotherapy remains to be seen, because the platelets do drop with these drugs. We’ll see; it’s…

 

IV               George, it’s a fascinating look into some of… just some of the topics you’ve dipped into here at the American Society of Hematology meeting; what sort of message would you give to cancer doctors; is it an optimistic message at the moment, coming out?

 

GC             Keep hoping. Well, I think that Man’s scientific knowledge, which has expanded over the last 30 years, logarithmically, is now, finally, paying off; you know, you have antibodies; you’ve got immunotoxins; you’ve got… I mean, you’ve got all kinds of new things coming along. Eventually they will hit.

 

IV               We’ve also heard here that some of these therapies need to be used differently, or considered for older patients who may have co-morbidities, for example, and that many of the studies in the past may not have been addressing this; what would you say to doctors about this?

 

GC             Well, I think the cyto-toxics, I think, all practising doctors who give chemotherapy realise that older patients are more vulnerable to the side-effects of chemotherapy, and unfortunately they shave the doses; they reduce the relative dose intensity; and the results are not as good; the more we have, let’s say, less toxic drugs… the best example of that is actually in the large-cell lymphomas that are presented here some years ago by Coiffier; when they added rituximab to the Chop regimen in old patients; and showed the marked improvement over chemotherapy alone when you add rituximab, which has no basic toxicity.

 

IV               So, how much scope do you think there is in improving therapies for older patients?

 

GC             Oh, I think there’s a lot of room; the safer the chemotherapy, the better you’re going to get; and so there will be less intensity; the… less tendency to modify doses; to change things like that; and if the drug is effective, then you will benefit from the effectiveness of the drug. But you have to remember that there is co-morbidity as well, in older patients: they have heart troubles; they have secondary cancers, and other things; and so, that you can’t change; what you can change is the tolerance to whatever is appropriate treatment at the time, by adding, if you will, a less toxic drug; and I think that is the great crusade: to find agents that are targeted to a specific, known, lesion in the malignant cell; that will do the malignant cell in without doing the patient in, basically.

 

IV               And ecancer Television will, of course, be attending the forthcoming meeting in Rome, in March in 2011; I hope you’ll be able to make it too, George; but meanwhile, thank you very much for being on ecancerTV.

 

GC             Not at all; glad to be here.