EHA 2015

Overview of innovation in Hodgkin's lymphoma

Prof Volker Diehl - Winner of the Jean Bernard Lifetime Achievement Award

You have just been given a very big award. I think of you, I think of BEACOPP, this very important regimen for Hodgkin’s disease and a whole lot of other things. What do you think the EHA is remembering you most for when they’re giving you this prestigious Jean Bernard Lifetime Achievement Award?

As I said in my thanking words, maybe two things. One that I am one of the still living old pioneers of Hodgkin’s disease and the other is that I was a bridge person between laboratory and clinical bedside, the patient. We started out with Epstein-Barr virus and found that it is absolutely a tumour virus in Burkitt’s lymphoma in Africa but we didn’t know what it does in Vienna or in Philadelphia at this time. We knew that it is a virus coming from a tumour therefore we tried to transform normal lymphocytes and I used umbilical cord blood cells and I put it on the tumour cells of Burkitt’s lymphoma patients and the virus was transferred and the cells were immortalised. This was in 1966, the first time that human lymphocytes were immortalised and this is with EBV, with Epstein-Barr virus.

How did that join up with the Hodgkin’s disease work?

At this time not at all. We later found out in Sweden that Hodgkin’s disease is connected with Epstein-Barr virus and about 50% of the Hodgkin’s patients have in their tumour cells the gene of the Epstein-Barr virus. But 50% don’t have it, that means possibly there is another ubiquitous virus that can cause Hodgkin’s disease but we don’t know it. Howard Stein, the Nobel Prize winner, and I have tried to find this virus in our tumour cells in vitro but so far we haven’t yet found it.

For some time BEACOPP has been the leading sparring partner to ABVD in Hodgkin’s disease therapy. Both have achieved amazing results. What gave you the idea of generating BEACOPP?

We were not excited about ABVD because if you give an advanced Hodgkin’s lymphoma stages ABVD six or eight times you get about 70% progression free survival but 30% will relapse or progress. We were not happy with that, therefore we tried to increase the density and intensity of ABVD or whatever, at this time it was COP-ABVD. So we put it together and it came out BEACOPP and we had a mathematical model and we could show that it is 10% better than ABVD. Then we did this study and it worked. BEACOPP is a very aggressive but very effective regimen that is used mostly in Europe. We have about 90-95% tumour free survival after ten years without using the transplantation that you have to use in about 30% after ABVD. Autologous transplantation is expensive, the patient doesn’t like to have a relapse, he wants to be free of tumour. They say, ‘Dr Diehl, you are very nice, we love you but we don’t want to see you again,’ so they don’t want to have a relapse. Therefore we use the BEACOPP but BEACOPP is too aggressive.

And thereby hangs a tale because BEACOPP is now changing. Can you tell me what it has changed to and what difference this is making?

Yes. When you asked me what is the most important invention or happening that occurred in my career, then it is most probably that with Howard Stein, my pathology friend, we found the CD30 antigen on the tumour cells, the Reed–Sternberg cells. For thirty years we tried to sell this monoclonal antibody that we produced against the Reed–Sternberg cells but nobody wanted it. The companies said, ‘Well, it’s nice but it doesn’t kill.’ So there came a chemist from Seattle, Seattle Genetics, and he put a bump on the CD-30 antibody with a linker and then this construct with this bump and goes in the tumour cells, it is released and kills the Reed-Sternberg cells. Since the Reed-Sternberg cell is keeping up the environment alive, the whole environment, even relapsing tumours disappear within 14 days. Therefore brentuximab vedotin is a new agent, the new magic bullet that already was asked for from early in 1928. He wanted to have a magic bullet that you don’t need radiotherapy and chemotherapy and you get rid of the toxic effects acute and long-term.

But now BEACOPP is changing, can you tell me what is happening?

We are happy with the efficacy of BEACOPP because it induces 95% of complete remission and 90% of tumour free survival after 5-10 years. But it induces also toxicity and it is leukaemogenesis, it is infertility and it is long-term toxicities cardiac and pulmonary. Therefore we decided to use the new antibody drug conjugate, brentuximab vedotin, put it in the early induction therapy BEACOPP and out of BEACOPP became BrECADD. BrECADD means brentuximab vedotin, etoposide, cyclophosphamide, adriamycin and instead of procarbazine we give dacarbazine and instead of prednisone we give dexamethasone.

Meanwhile, what has happened to the whole ABVD side of the story?

The ABVD side of the story is changing also because they’re using brentuximab vedotin now and they leave out the bleomycin and give AVDA – adriamycin, velban, dacarbazine and brentuximab vedotin, ADCETRIS it’s called in America. AVDA is now tested against ABVD and it seems that it is very effective and less toxic than ABVD.

Finally, what do you advise doctors to make, clinically, of these very interesting developments?

Both the AVDA using brentuximab with ABVD or BrECADD is not yet on the market. It is in clinical studies and there is an ECHELON-1 study ongoing with Takeda and we will start next month the BrECADD study with Australia and some European countries. In about two or three years we can tell you whether we can stop BEACOPP and we will have BrECADD and AVDA.

Now, very, very briefly could you run me through the numbers? How much of an improvement in therapy for Hodgkin’s disease and preservation of the reduction of long-term toxicity might this all mean?

AVDA, they want to go from 70% complete remission to 81%. For us it’s not enough, we need 90 or more, 95. BrECADD will have about 90% complete remission induction and about 40% only toxicity. That means half of the toxicity but the same efficacy with BrECADD.

Could I, though, ask you about nivolumab?

There are two studies that were reported at ASH 2014 by Ansell and Moskowitz.  This is one of the new drugs that activates the T-cell response to tumour cells. Nivolumab is an antibody that inhibits the programmed death interaction between the tumour cell and the T-cells. So if you inhibit that, then the T-cell will be activated and kill the tumour cells with the result that you have about 80% of response now without even chemotherapy.

Could you potentially use nivolumab together with brentuximab?

Possibly. This will be one of the studies to have this cocktail and I’m sure that already some studies have started to do that and leave out the chemo and radiotherapy.

So what’s your takeaway message for doctors?

The takeaway message is use ABVD in early stages, possibly leave out the bleomycin because we have shown that AVD is as good as ABVD. In the very aggressive advanced stages use two courses of BEACOPP escalated then make a PET. If the PET is negative go to ABVD. If there is a very aggressive advanced Hodgkin use BEACOPP all the way through. And wait until we have AVDA on the market and BrECADD or AVDA.