EHA 2016
Advances in first line treatment options for MCL patients
Professor Steven Le Gouill – University Hospital of Nantes, Nantes, France
Professor Simon Rule – Derriford Hospital, Plymouth, UK
SLG: I’m Steven Le Gouill from Nantes Medical University and I’m here with my friend, Simon Rule from Plymouth University in the UK, and we are going to discuss about mantle cell lymphoma. In the oral session there were two very interesting presentations today, one presented by you Simon. So you talked about the RAY trial, could you please remind us what was the RAY trial?
SR: The RAY trial was recently published in The Lancet, which I presented at ASH, which was a randomised trial between ibrutinib and temsirolimus in patients with relapsed refractory mantle cell lymphoma which showed a very clear progression free survival advantage for patients with ibrutinib. The interesting thing with that trial was what I presented at ASH but wasn’t in the publication which looked at outcomes by prior lines of therapy, showing very, very clearly that the earlier that patients were treated within that trial the better the outcome. So what we’ve done in this presentation is pooled the data in the RAY plus the SPARK trial, which is a single agent trial with ibrutinib in patients who failed Velcade, and the original 1104 trial, so the first trial with ibrutinib.
SLG: How many patients?
SR: So that’s 370 patients all together, so all relapsed refractory mantle cell lymphoma, pooled and then looked at overall survival, progression free survival, by baseline characteristic. Now what we know with ibrutinib and I think what everybody recognises is that 70%-ish is the response rate across the board. We saw with SPARK, although that’s not been published yet, that the blastoid patients did worse but beyond that we knew that it didn’t matter what the baseline was the patients all responded. So what this study does which is rather nice is it takes all those baseline characteristics and looks at progression free survival and overall survival. It shows what I guess you might expect, that the patients with the bad disease, so blastoid patients, bulky disease, high risk MIPI, those characteristics do worse and they do worse with respect to progression free survival and overall survival. So response rate is the same, or broadly the same, but bad factors with respect to disease play out with progression free survival and overall survival. That’s a very important point, we are tricked into thinking that if we use the drug later on, because we get such a high response rate, that’s good but actually if you look at duration of response and we look early, so if you look at first relapse it’s hugely different progression free survival and overall survival than if you use it later on. The other thing that is really probably the most interesting slide in the whole presentation is if you look at response. So if you get a complete remission on ibrutinib you have an extraordinary PFS and overall survival. So over 90% of patients who get a CR are alive at two years.
SLG: And you get a plateau or do you still observe late relapse?
SR: No, you’re still seeing if you look at the PFS you’re seeing patients still relapsing so there’s no plateau but it’s striking how high that curve is in that CR group of patients. So if you do well you do extraordinarily well. That lends itself to what next, so the CR rate is about 20%, it’s slightly higher actually, so for the first time we show in this study that if you use the drug first line you get a higher CR rate than if you use it later on. I guess that’s not a surprise. So if you push people to a CR, so by adding maybe rituximab, so we know Michael’s data adding rituximab doubles CR.
SLG: It was very good results.
SR: Very good results, will you then see that translated into that same curve? Then the next obvious line is if you’re seeing that at first relapse are you going to see even better front line?
SLG: OK, so the next step is front line, as you mentioned, so the earlier you receive ibrutinib, maybe with or without R, the better results you get. So I think this is what you are doing now in the UK, you started a trial called ENRICH, am I right? Could you please tell me a few words about this trial?
SR: Yes, this is using ibrutinib rituximab first line but randomised against standard of care and the standard of care, we’re talking older patients over the age of 60, so this is not the autologous stem cell transplant group of patients. So it’s either bendamustine or CHOP with rituximab with maintenance versus ibrutinib rituximab. It’s just started, there are only three patients in the trial so far but it’s going to open across the UK and subsequently in the Nordic countries as well.
SLG: So the analysis you performed on the RAY trial and the other trial is clearly supporting this approach that you have in your ENRICH trial. You said that there is no plateau, that you observed early response and late response. Do we know something about who are these patients who have early response and late response? In the session George from Germany presented some results, what is the taking message from this presentation?
SR: George was looking at gene expression and a whole range of genetic abnormalities with patients.
SLG: Yes, it’s a large analysis.
SR: Those that were primary resistant, those that got partial responses, those that did well. As I was telling you before, and I was talking to George only an hour ago, and he’s not sure what to make of it. Basically the mutations that patients get are in the NF-kappa B alternative pathway, so that kind of escape mechanism, but they’re not all there and they’re in all sorts of places. The abstract says that there aren’t any in BTK binding sites but actually there are, there are a couple.
SLG: It has been observed.
SR: And that might be you see those in CLL but they’re on the drug for longer. So it might be that patients who are on the drug in mantle cell lymphoma for longer you might start seeing those. I guess as we use the drug earlier on patients are definitely going to be on the drug for longer. So I’m not sure what to make of that yet, I think the clinical characteristics we recognise such as blastoid variant and bulky disease and MIPI, right now that trumps any kind of genetic data that we might have. It’s interesting but I’m not sure it’s terribly relevant at the moment.
SLG: So we’re not ready for a genomic driven strategy yet, it’s too early.
SR: The one group I should perhaps emphasise is the blastoid variant. So about 12% of the patients in this study have blastoid disease, they clearly do much worse. So there’s a 55% response rate and the duration of that response is 5 months so it’s short. Overall if you take the whole group it’s over a year. That’s of relevance in a patient so we’re using it at relapse, you give them ibrutinib, it’s still the best drug we can use in that group of patients, but you’ve got a window of five months and if you want to do an allograft you need to get on and do it sooner rather than later. So it’s an ideal bridge to a transplant in a young, fit person with blastoid disease but you really need to do it quick.
SLG: So let’s go on with the allotransplant programme. Some information so far about allotransplant up front, please could you comment on these results?
SR: We’re presenting the data here on a front line mini allotransplant study in mantle cell lymphoma. It was an oral presentation at EBMT, actually, a month or so ago. What we did, and it’s quite an old study now, it’s pre-ibrutinib, we generally accept that allogeneic transplant is the thing to do in a young patient who has relapsed after an autologous stem cell transplant. We perhaps cure a proportion of those patients but of course that comes with toxicity and graft versus host disease and all those kinds of things which we’re comfortable with in a setting where you’ve relapsed after an autograft and you really don’t have many options. So this was front line, 25 patients and to get to the transplant, which was a BEAM-CAMPATH conditioned mini allograft…
SLG: So you used CAMPATH so you’re not afraid about T depletion induced by CAMPATH?
SR: No because it was related and unrelated patient transplants. The patients went into that study with a CR or PR from whatever treatment they’d had beforehand so that was permissive. So you come in, you’re young, fit, you’ve got a donor, be it related or unrelated, you have a BEAM-CAMPATH transplant and basically we saw what happened. Broadly these are young patients, of course because they can have a transplant, the transplant related mortality was only 8% which is good, we shouldn’t really be killing people with our front line therapy but, you know, the inevitability is even with the type approaches that does happen. Basically at three years 70% of patients are alive and disease free. The curve looks very encouraging, we know a quarter of those patients have got chronic graft versus host disease.
SLG: Which will impair the quality of life for patients.
SR: It certainly affects quality of life. Now that’s interesting; in five years’ time when we have eight years follow up if that’s maintained then that’s very interesting. What it shows is it’s feasible, we knew that anyway. The question is is this a valid study today with these new drugs around. I think what it says is you can do this and you get durable responses in patients, transplant related mortality is low using this approach. If we could pick the patients that we know are going to do badly, and I think in a very young patient with a blastoid type disease I would be very tempted to do an up-front mini these days. I know you prefer to do an autologous stem cell transplant and then do an allograft when they relapse, I understand that, but I’m quite impressed by that data.
SLG: I think the issue is allotransplant, as you mentioned, is a toxicity. The TRM, 8% is not nothing even if it’s not as high as has been reported by some groups. The other thing is the quality of life after the transplant and one thing we have to keep in mind is that allotransplanted patients are often not included in clinical trials because this is an exclusion criteria. So if you chose to go to allo up front to the patient, which might be a solution for some of them, you also take a risk not to be able to propose new drugs in clinical trials for these patients. So there is a risk they’d have to be well measured but that could be approach for some patients. So we said yesterday that autologous stem cell transplantation still remains the standard of care; today we can’t say that allotransplant is standard of care.
SR: No, no, I’m not advocating it at all. I think what it showed was the feasibility of the approach in that group of patients and if we could be smart about picking the patients that aren’t going to do well it’s something worth exploring.
SLG: But will we be able to do that because some of these results from are a little bit disappointing, not the quality of the data here, it’s very interesting work, but we expected to find something more clear-cut for clinical use which, unfortunately, is not the case.
SR: No. The bottom line is we’re going to give these drugs and see if they work, aren’t we? That’s what we’re going to do, we’re not going to do a gene expression analysis and say, ‘Well you’ve got this, this and this,’ this isn’t Herceptin, there isn’t something very clear that there’s a target that you will use or you won’t use. Of course adding chemotherapy, we know BR plus ibrutinib looks extremely good. We imagine SHINE is going to be positive, I guess.
SLG: Yes, we can guess.
SR: So SHINE is BR plus ibrutinib.
SLG: Maybe ENRICH too but it will take a long time.
SR: ENRICH too. ENRICH then becomes interesting because if SHINE is positive then I guess the standard of care becomes bendamustine rituximab plus ibrutinib and the question is do you need the bendamustine? That’s where our study comes in, I suppose. In older patients you probably don’t. As we said yesterday, chemotherapy for young patients is standard of care, we accept that. In older patients responses aren’t that durable, toxicity is more of an issue, so using a new drug, maybe with an antibody, is all one needs.
SLG: So a lot of very interesting data in EHA and I know we should go on with this conversation at ASH.
