2011 ASH Annual Meeting, December 10-13, San Diego, USA

The changing landscape for NHL treatment

Professor Bertrand Coiffier – Hospices Civils de Lyon, France


Welcome to ecancer.tv. My name is Keith Stewart, I’m a Professor of Medicine at the Mayo Clinic in Arizona. We’re here today in San Diego at the American Society of Haematology 2011 Annual Meeting and we’re going to talk today about the use of bortezomib in follicular lymphoma. Dr Coiffier, welcome.

Thank you, welcome.

Would you start by telling us a little bit about the phase III trial that was the basis of the abstract you’re presenting here at this meeting?

Yes. The first results were presented last year at the same meeting, at ASH. It was a randomised study in relapsing follicular lymphoma between bortezomib plus rituximab versus rituximab alone. It was a large phase III study in several countries around the world and it showed several things interesting. The first one, it was the first randomised study looking at the effect of rituximab alone in this population of patients. The second is that it showed that bortezomib plus rituximab had an efficacy, if you look at the response rate or progression free survival, particularly in patients with adverse prognostic factors. These were patients with a large tumour burden and the classical prognostic factor that you see in follicular lymphoma.

How many patients were on the trial roughly?

It was 600 patients.

Tell us about the abstract you’re presenting this year at the meeting which looks at biomarkers as part of this clinical trial.

Yes, this year I present a characterisation of biological factors associated with response to bortezomib plus rituximab in these relapsing follicular lymphoma patients. We have looked at a lot of biological factors and find that a few, only a few, nine had some interest when you look at the biological factor alone. We tried to combine two by two the different biological prognostic factors that we have found and at the end we have only one pair that is statistically associated with a longer survival. This pair is a combination of one genetic factor that is a proteasome sub-unit and also a classical marker that had already been described in follicular lymphoma – the presence of CD68 positive cells.

So activation of NF-kappa B in the proteasome predicts for responsiveness?

Yes.

Is that correct? And what was the difference? How predictive was the finding?

In fact it is only if you look at the positive pair, that is patients that have both parameters. There is a large difference between the two groups, that is patients that used bortezomib plus rituximab versus rituximab alone and if you pick the patients that are negative, that have not any characterisation of these two parameters, the outcome is similar, that is of no difference at all between progression free survival or response rate.

So it’s highly responsive for the bortezomib side of the equation. Was this progression free survival or overall survival or both?

It’s progression free survival.

Progression free survival. And how much is it extended, roughly, if you have these markers present and you receive bortezomib versus Rituxan alone?

It’s six months difference between the two, median progression free survival.

Is this a clinically viable prognostic tool? How do you measure the… is it gene expression or…? I know the flow cytometry for one but how do you measure the proteasome sub-unit?

Yes, it’s a genetic analysis so for the moment it’s not easy to do. We are working to have a simple test to measure it and to know what the allele… there are two alleles for these genes and to look at the alleles is easy but for the moment it’s quite difficult to apply before treating new patients. But in the future we would hope that what we are doing will allow to have this measure really easily. The macrophage, the presence of macrophages is easily done by the pathologist so in a few months it will be easy to look at the patient and say, “This patient will respond to bortezomib, this one will not respond,” and treat only the patient that will respond to bortezomib.

Now, if bortezomib was widely available to you to use, what do you think its role is in the management of follicular lymphoma? Should it be restricted to relapse, used earlier and in what kind of patient would you use it?

For the moment bortezomib is not used in first line patients with follicular lymphoma. I’m not aware of any study with this drug in first line patients. All the studies that have been done are on relapsing patients and it has efficacy on relapsing patients. There are several biological drugs that have efficacy on relapsing follicular patients, bortezomib is one of them and if the patient has the characteristic associated with response, I think it should be used. I’m not sure if it is a second line, third line or fourth line but as all these biological drugs have efficacy but not cure and the patient has an efficacy for eighteen months at the median, so you have to use them sequentially. So bortezomib may be the second, the first or the third, as the physician prefers.

My last question is what trials are on-going to further define bortezomib in this disease?

For the moment there is not anything designed that we’re working on. Certainly we have an interest to look at the proteasome sub-unit and the allele of this protein. We may organise a study based on the patients that will respond and try to associate another drug, probably, to improve the response rate in this group of patients.

It’s interesting, I’m a myeloma doctor mainly and, of course, we don’t have good predictive markers for use. It would be very interesting to look at those two markers in myeloma now to see if the same thing holds true.

I’m not sure for the macrophages because there are less macrophages in multiple myeloma but when I get these results I try to look at the patients with multiple myeloma and to look if the same study has been done in multiple myeloma. And I was surprised not to find it.

We don’t even measure CD68 on the surface of the cells.

No, but to look at the proteasome sub-unit alleles, I think you may probably find the same thing, that is something that responds better if they have some abnormality. Because the characteristic of this sub-unit is that if you have not got the good allele, the proteasome is not very well assembled. So it’s not functioning correctly.

Well it certainly sounds like something we should explore going forward.

Yes, certainly.

Thank you for your time today and thank you for joining us at ecancer.tv