Franco Cavalli, thank you very much.

A pleasure.

Not just for talking to ecancer about this nice trial that you’ve been running but for forty years of lymphoma leukaemia research which you’ve been at the front of as long as I can remember. When you and I started looking after lymphoma patients forty years ago there was just CHOP and not a lot changed until we got rituximab-CHOP but now we’re seeing another field change, we hope. First of all tell me about mantle cell lymphoma because not a lot of people see a lot of patients.

Mantle cell lymphoma is a rare subtype of lymphoma comprising about 6% of all non-Hodgkin’s lymphomas. It’s still considered to be incurable. We have made some progress in the last years, mainly by treating patients with more aggressive treatment compared to CHOP and by adding, in responding patients, high dose chemotherapy with autologous bone marrow transplantation. But the progress has not been great; mantle cell lymphoma is still considered the worst subtype of aggressive lymphomas and the median survival for at least 90% of patients who have an aggressive form, there are 10% with an indolent form, but the 90% of the patients who have the aggressive form the mean survival time is still somewhere between three and four years.

And we’ve been looking at new drugs, you’ve been looking at new drugs all your career and bortezomib came along and seemed to show activity in failed patients with mantle cell lymphoma, is that right?

Yes.

Are these transplant patients or people who didn’t get transplants?

Both.

Both, yes.

Both transplant patients and patients who didn’t get transplanted. There are three or four interesting new drugs for patients relapsing, the first one was bortezomib, then lenalidomide came along and now ibrutinib is the last one which has produced interesting response rates in relapsing patients. But bortezomib has been the first really new drug which had a consistent and important percentage of response in relapsing patients. So it was normal to try to incorporate bortezomib in the first line treatment.

And so you put it into newly diagnosed patients not fit for transplant and the standard treatment, of course, was CHOP-rituximab and then what was the thinking behind V-CAP?

Velcade is a drug which is somewhat similar to vincristine, it has also a similar toxicity profile with neuropathy like vincristine, so it was logical to try to substitute vincristine with bortezomib in the R- CHOP combination chemotherapy. The trial was performed mainly in China, in Russia, in the eastern part of the EU but about 25% of the patients were treated in Western Europe. So a total of almost 500 patients were randomised between the classical R-CHOP and the new treatment where instead of vincristine bortezomib was used, 1.3mg/m2 in that study is that since the limit for bone marrow transplantation was set at 60 years and in some of the centres participating through the study there was not the possibility to transplant patients the population which has been treated is rather similar to the normal population of patients with mantle cell lymphoma.

That’s very informative.

Yes, it’s very informative. If you see the median age is 66 years which is exactly the median age in most of the series.

In the population.

There is a relation three to one for males, three males and one woman, which is again what we see in the lymphoma database. Also the percentages for stage 2, stage 3, stage 4, IPI, subgroups and so on are exactly the same. So it’s a very informative trial.

And it’s a big trial. I can’t remember ever seeing a mantle cell trial with that number of patients in it. It’s really an impressive effort.

It is a big effort. Yes, it’s an impressive effort; it’s the biggest trial which has been carried out up to now in non-previously treated patients with mantle cell lymphoma.

And there’s an interesting outcome too otherwise we wouldn’t talk about it.

Yes, the outcome is interesting because there is a clear-cut and highly significant difference in the progression free survival in favour of the new combination treatment including Velcade. The median progression free survival in the R-CHOP is in the order of 17 months; in the Velcade arm it’s almost 25 months which is an improvement of almost 60%. And this is by the data provided by the independent review committee; based on the investigator it’s even bigger, the median there is 30 months. And if we consider only the patients who are younger than 60 and who did not have medical reason for not being transplantable the median in the Velcade arm is 44 months which is almost exactly the same as the best results which were recently published by the Eastern Co-operative Group with an older Velcade encompassing regimen but which was more intense and more aggressive than this one.

That’s a very impressive result. And the downside? Toxicity comparisons? What about the neurotoxicity issue, vincristine versus bortezomib head on?

The Velcade arm had somewhat more general toxicity but not neuropathy; the neuropathy is exactly the same percentage-wise. The interesting point, which is a bit striking, is that the neuropathic symptoms seemed to resolve quicker and in a higher percentage in the Velcade arm as compared to the classical R-CHOP. Of course there is more myelosuppression so many more neutropenia, more thrombocytopenia in the Velcade arm but there is no increase of bleeding. There is a little bit more of infectious complications but looking at the number of patients who had to discontinue the treatment because of toxicity and at the drug-related deaths they’re exactly the same in the two arms.

And that’s with 75% of the patients over 60?

Yes.

In a group who you would expect maybe would have done worse. And I think there were two deaths in one arm and three deaths in the other arm?

Yes.

So that’s a fair result, I think. So have you seen anything like this before in mantle cell lymphoma?

No, the data are still not mature enough as regards overall survival.

To give you survival, sure.

At four years there is a 10% advantage of the Velcade arm as compared to the other arm but it is too early because only about 30% of the events, as regards survival, have occurred. But the two curves are separating so my impression is that possibly when the data will be more mature there will be most probably a difference also in overall survival, which would be new in mantle cell lymphoma.

Yes, absolutely. How are you going to handle the fact that you’ve got possible active drugs for those who fail? Have you got a policy ready for people who fail on either arm to get a new active drug, one of the lenalidomides or one of the others?

No, there was no policy but looking at the subsequent treatment there is no great difference in the treatment which the patients received in both arms. The accrual stopped in 2011 and some of the newer drugs like ibrutinib were still not available.

Sure. Is this a paradigm shift?

I think that one could say that most probably, well we have still to wait a little longer, but most probably the new R-CAP regimen is going to be considered the standard treatment at least in the patients who are not eligible for more intense treatment and for transplantation.

Congratulations to you and to your international group, stretching right across half of the world. Well done.

Thank you.