SR: You’ve got a very interesting abstract here, a presentation you’re giving tomorrow, on the addition of Velcade to CHOP in front line treatment of elderly patients with mantle cell lymphoma. What are the key messages from that presentation?
FC: I have first to say that it’s not in addition but it’s substituting vincristine which is important for the discussion about the toxicities. So it is a novel combination whereby bortezomib is in place of vincristine in the classical R-CHOP treatment for elderly patients with mantle cell lymphoma. The crucial point is that by basically the same toxicity the outcome is much better with the new combination including bortezomib. The PFS, progression free survival, has improved by about 60% if we look at the data as generated by the independent radiological review committee. If we consider just the investigator data the improvement is about 100% and at this moment in time it is too early to tell about overall survival because the median follow-up is just 40 months. The curves are still diverging; for the time being the difference is not yet significant but my impression is that it will become statistically significant as the follow-up goes on.
SR: Velcade is clearly an active drug in mantle cell lymphoma and I often add it to chemotherapy if chemotherapy is not working. If you look at all the studies where Velcade has been incorporated it seems to be synergistic. So I’m not really surprised at the outcome of that study but one of the issues is the way the Velcade was given so it was twice a week in a standard myeloma schedule. Do you think, because one of the issues was thrombocytopenia, there was quite a bit of thrombocytopenia in the Velcade containing arm, do you think the scheduling had something to do with that?
FC: Probably, yes. It is true that there was more thrombocytopenia but there was not more bleeding. So this was asymptomatic thrombocytopenia. Yes, I think that the regimen could be further improved on the one side by using Velcade sub-cue and not IV which would probably decrease further the overall toxicity. On the other side, it might be that mainly if you keep also vincristine to use the weekly instead of the two-weekly schedule it could probably further decrease the toxicity. I’m not sure that this is going to change the rate of complete responses but I know that you have some data and that, to my surprise, it does seem that by adding bortezomib to the classical R-CHOP, still including vincristine, if you use a weekly schedule this is not increasing the neurotoxicity; I would have expected the contrary.
SR: Yes, so we did a study which is about to be published in the UK which was in first relapse mantle cell. It was CHOP versus CHOP plus Velcade, rituximab wasn’t in there, it was an older study, which showed a survival benefit for the addition of Velcade, which was a big surprise to us, but no additional toxicity. There was slightly more low grade neurotoxicity but no significant increase in grade 3 or grade 4 neurotoxicity. So giving it weekly, 1.6, that was IV and I’m sure if we give it sub-cue you’d have even less so the addition of the Velcade to the vincristine wasn’t an issue. There were anxieties when this study was started that that was going to be a problem and I’m not sure that it is if it’s given weekly. What do you think is the take home message, then? Do you think this is now, as one would call, the standard of care for older patients?
FC: I think we have still to wait a little bit for the overall survival data to mature but it could become the new standard for the usual patients with mantle cell lymphoma. In our study the median age was 56 which is the median age of the novel patients with mantle cell lymphoma who come to your door. So I think, excluding the 10-15% very young patients where you can consider a much more intense treatment, in the vast majority of patients with mantle cell lymphoma that could become the new standard of treatment.
SR: What people will point to is that the CHOP rituximab with rituximab maintenance gives better results but there was no maintenance in this study and you would expect maintenance would probably double the PFS, that’s what you saw with the CHOP-R study. So that regimen, probably with the addition of maintenance, may well be better still.
FC: Yes, I think that maintenance is probably of importance in mantle cell lymphoma. I don’t know if this is for all patients or for the indolent part of mantle cell lymphoma, that might be the part which had more of an advantage in the Scandinavian study, but the next question in my opinion is then how can we further improve the data either by adding a maintenance or by including a drug like ibrutinib which seems now to be very interesting in the treatment of mantle cell lymphoma.
SR: So that’s a perfect introduction to my abstract which was the long-term toxicity of ibrutinib within the mantle cell lymphoma phase II study. This is looking at the toxicity in patients who have been on the drug long-term and although there’s no efficacy data in this abstract, it’s just looking at toxicity, it’s interesting that in a heavily pre-treated group of patients half of them were on drug for over a year and a quarter of patients are still on drug over two years. So very well tolerated and still obviously efficacious enough in a very heavily pre-treated group of patients. So what this abstract does is actually document the toxicity and the side effects that people have had concerns about, I think it’s quite reassuring. So diarrhoea, for example, when that’s presented you see over 40% of people get diarrhoea and what the abstract actually tells you is that it comes on at a median of 8 days and it’s gone 5 days later and that has certainly been my experience – it’s very modest, it comes on early and it goes. If patients stay on the drug, once you get beyond six months these side effects are disappearing. The same with fatigue, these are minor grade 1/grade 2, they’re largely going at three months, at six months. What people are concerned about – infections. Again, infections disappearing once you get beyond six months, no impact on immunoglobulin.
FC: My main concern would be in the usual population of mantle cell lymphoma, I don’t remember the median age in this population…
SR: It’s 68 again, something like that.
FC: 68 again. My main concern would be in these patients the bleeding because all of them take aspirin.
SR: I was coming on to that. So bleeding remains constant, it’s 5%. So risk of serious bleeding is 5% but it’s bruising is what people get, contusion, not active bleeding. Four patients on that study had subdural hematomas and that was very early on and they were all associated with trauma or head injury, falls, and all those patients were either on aspirin or warfarin, mostly on warfarin, so the decision was taken then that warfarin became a contraindication to the study. But bruising is certainly an issue, about 50% of people get some kind of bruising and, again, that’s been my experience that they’re mark bruises, a bit like you see… very elderly patients often bruise easily, it looks a bit like that. Sometimes it’s quite impressive. I had a guy who had some very impressive bruises on his arms but he was in complete remission, he felt great, he didn’t care. So I’m not too worried about that side of things. The one thing you have to remember is not use it with warfarin.
FC: With just warfarin or all kinds of anticoagulants?
SR: Warfarin is what people are… the main issue. On the label in the States it says caution with these agents. It’s a balance of risk with these people. The other thing is to stop the drug a few days before any kind of surgery; there has been bleeding associated with surgery so you’ve got to stop and then restart. There’s some kind of platelet interaction going on there so it’s an issue but it’s not a major issue and bruising, you just have to warn people that bruising is going to become a potential issue. But it works so well and patients feel good on it, you just have to explain and it’s a balance of risk, bruising versus very active treatment. So what’s going happen next is ibrutinib is going to get incorporated into chemotherapy and then you wonder if the abstract with Velcade is very quickly going to be superseded by bendamustine, rituximab plus ibrutinib, for example, something like that.
