EHA 2015

Immunoconjugates address unmet needs in Hodgkin's lymphoma patients

Prof Anton Hagenbeek - University Medical Center Utrecht, Utrecht, Netherlands

In Hodgkin’s disease quite a lot has happened; there is a lot of talk about making therapies more gentle and you’ve been looking at an immunotherapy but a particular kind of immunotherapy. Can you tell me what this is and why, first of all, you thought this was a good avenue to proceed down?

Well it’s not only me, this is a worldwide development of haematologists that take themselves seriously. You can capture it under the heading of targeted treatment, not only in Hodgkin’s lymphoma but also in the leukaemias, in the non-Hodgkin’s lymphomas, multiple myeloma, that is the new way to go, I personally feel. If we focus on Hodgkin’s lymphoma there is a specific structure on the surface of the cell that is called CD30, we call it an antigen, and now there are available antibodies against that CD30, a target antibody and very effective cytostatic drug, it’s attached firmly. So if you inject the whole complex into a patient with Hodgkin’s lymphoma that complex will link to each and every Hodgkin’s cell that has a CD30 and that CD30 links to that. What the cell then does subsequently, and it’s a stupid move, is to internalise the whole complex and even splits off the cytostatic drug from the antibody. So it’s a Trojan horse that comes inside and the cytostatic drug comes out freely and kills the cell immediately, very effectively.

Can you tell me what the latest is on brentuximab vedotin, then? What exactly it is?

It started, of course, in patients that had had previous treatment like autologous transplantation, had relapsed multiple times in Hodgkin’s lymphoma, and it turned out that about 96% of those patients responded favourably with a significant reduction in tumour load, about 45% complete remissions in this unmet need population of patients where we didn’t have anything else. Never seen something like that before with a single agent in this dreadful population of patients. The same holds for a subtype of non-Hodgkin’s lymphoma, anaplastic large cell lymphoma, also CD30 positive because that’s a prerequisite - treatment with response rate in patients in the terminal stage of the disease with another chance to be cured. So I think exciting developments there.

Now ABVD has for a long time been the team to beat. What is happening because of these immunoconjugates?

That’s a good question and not only ABVD but also BEACOPP that was developed by our German friends, the German Hodgkin’s Study Group, and that is used by several centres worldwide; ABVD has been used more frequently so far. The whole move is to replace several of those, let’s say, most toxic compounds of ABVD or BEACOPP by brentuximab vedotin. The randomised trials are going on, to give you one example there are several randomised trials comparing ABVD as the conventional treatment arm with AVD plus brentuximab vedotin, plus the antibody drug conjugate, to see whether that’s even more effective. BEACOPP undergoes the same modification, taking out some of the alkylating agents that may cause late effects like secondary leukaemias and replace them by the much more safe brentuximab vedotin.

How much indication is there, or what quantity of improvement in late toxicities might you get from migrating towards these immunotherapy based treatments?

We don’t know that yet, exactly, the long-term effects because it’s not that long, we don’t have that long an experience with it. But what I can tell is the side effects are manageable from brentuximab vedotin as a single agent to start with, that means there is some neutropenia but we know to handle that on a daily basis being haematologists, nothing new. There is some neuropathy, mainly grade 1 and 2 because some of the drug may leak out of the cell and hit the nervous system so you get tingling of the fingers and that feeling under the feet, things like that comparable with the old-fashioned vincristine that we know very well from the CHOP chemotherapy. So the therapeutic index, as we call it, is quite high, that means a very high efficacy and a low tolerable toxicity.

So what should doctors take away from these developments then?

I think they should take away, if you talk about Hodgkin’s lymphoma I’m convinced that these patients should primarily be treated in trials and not just ad hoc. So I would suggest if possible to join a trial in the first line to start with, up-front treatment where brentuximab vedotin is being explored.

So, of course, Hodgkin’s disease is one of the big cancer success stories so how much are you going to improve on success?

We have always there the unmet need population in Hodgkin’s lymphoma that is not cured right away by the first line treatments. We need to improve on that because of relapsing patients or primarily refractory patients we can only cure about 30-40% with autologous transplantation. So there’s an unmet need there, but to take your question one step further there are also a number of other malignancies that are CD30 positive and might be eligible for this effective treatment like about 25% of diffuse large B-cell lymphomas that have relapsed. We have a high unmet need there, we don’t know how to treat those patients so we should add brentuximab vedotin to second line treatment to make it more effective and make more patients eligible to go to an autologous transplantation that can be curative. There are a variety of T-cell lymphomas that are CD30 positive, including the skin lymphomas of T-cell origin and some dramatic responses have been described there as well. So there is a whole variety of haematological malignancies that are eligible for exploring the brentuximab vedotin efficacy.