JG: This is John Gribben reporting from a very warm Milan where we’re at the European Hematology Association meeting. I’m joined today by Steve Mulligan from Sydney and Pete Hillmen from Leeds and we’re going to update you on some of the things that we’ve been hearing new at EHA as well as touching also on some of the things we heard at ASCO just last week. Exciting times in CLL, I think we can safely say, in terms of the new drugs which are emerging and of course one of the big breaking news here was the results of the long awaited randomised trial looking at ibrutinib versus ofatumumab. You presented that data, Pete, do you want to take us through what are the highlights from that study?
PH: As you say, we’ve had phase I/phase II data on ibrutinib in CLL for probably two or three years now and we presented the RESONATE trial which is the first of the randomised phase III trials in relapsed refractory CLL. So for our relapsed trial we included 391 patients who were randomised between oral ibrutinib versus ofatumumab at the standard dose for relapsed refractory disease and included patients who were really unsuitable for chemotherapy, either because they’d failed chemotherapy before, and they’d all failed chemotherapy before, or 17p deleted or too old to have fludarabine-based chemotherapy. The results of the trial were that there was a massive difference, really, in progression free survival. In the interim analysis the trial was closed, the median follow-up was nine months, just over nine months, in both arms of the trial. In the ofatumumab arm the median progression free survival was just over 8 months and virtually all the patients had progressed by 12 months, which is what we’d expect from the phase II data of ofatumumab. With ibrutinib over 60% of patients remained progression free at 12 months and, in fact, over 85% of patients remained on therapy, so even the ones who had technically progressed were actually still responding to the treatment. The subsets, if you like, the resistant patients, the 17p patients, all showed a significant advantage in progression free survival as well. The overall, which was, of course, very impressive, the overall survival data, given that 57 of the patients in the ofatumumab arm crossed over to ibrutinib, showed a significant improvement in overall survival with 57% reduction in deaths in the ibrutinib arm compared to the ofatumumab arm. Once you got on to ofatumumab the curve plateaus out in the same way as ibrutinib so that it looks like it helps those patients who cross over.
JG: I guess in many respects the study is almost a victim of its own success in that it completed, hit the end points, so rapidly that we don’t yet have a terribly long follow-up. I guess that’s an issue that we’ll come back to talk about with all of these novel agents is that although we’re clearly excited by the results we aren’t yet seeing long follow up in terms of both the long-term effects on the disease control but also the long-term effects of potential toxicity. Are there any kinds of signals that you’re seeing that are of any concern, however, with the follow up that we have?
PH: I think you’re right, you allude to the fact that we’re trying to get these trials done quickly so that we can really get the benefits to patients as soon as we can but we have to really watch the long-term toxicities. In terms of the toxicity in the trial, the ibrutinib was very well tolerated and we saw adverse events but very few patients stopped because of the adverse events, to stop therapy. The only significant adverse event was an increased risk of mainly bruising and [?? 3:46] and that was seen in almost half of the patients. But it was all grade 1, largely didn’t cause a problem and only one patient stopped because of a bleeding problem. Actually, in terms of grade 3 and 4, so serious bleeding complications, they were balanced between the two arms.
JG: Yes, that had been a previous concern from the phase I/II studies. I guess the value here of doing the controlled study is to suggest that we weren’t seeing any additional signal over the ofatumumab, suggesting it’s probably more related to the disease itself and the patient population rather than to anything to do with ibrutinib.
PH: That’s right. The other major issue, well not major issue but the thing we have to be aware of, is that there’s an increased risk of diarrhoea in the first month or two of treatment. But this is very self-limiting, doesn’t seem to cause a problem and doesn’t usually require intervention and then over a month or two it usually disappears.
SM: So diarrhoea and arthralgia are the most common complications but both of them relatively mild in degree. There was also this small group of patients that developed atrial fibrillation on the drug, that probably wasn’t that well recognised previously.
JG: Maybe again a class effect of the kinase inhibitors.
SM: Possibly.
PH: So about 3% of the patients in the ibrutinib arm developed AF. Actually, four of those patients had actually had preceding atrial fibrillation and eight reverted to sinus rhythm anyhow, with treatment or without. Only one patient stopped because of the arrhythmia. So I think it’s manageable but it’s clearly in excess of the atrial fibrillation seen in the ofatumumab arm.
JG: We’ve also seen data presented about the ibrutinib failures and are beginning to understand some of the mechanisms whereby that may be occurring. Do you want to tell us about that?
SM: That’s correct. There have been a couple of presentations, one from John Byrd’s group, looking at ibrutinib failures and they tend to fall into a number of different classes. There are patients that develop Richter’s syndrome and they tend to develop fairly early. Then there are those with disease progression of their CLL and they appear to occur relatively late. Of the six patients that were tested by next generation or deep sequencing, in fact all of them had a mutation in either the BTK molecule or the PI3 kinase molecule.
PH: PLC gamma 2 was the -
SM: That’s right, yes.
PH: I have to say, when we looked at the RESONATE trial, the randomised trial, with a relatively short follow-up, as you mentioned, but they tend to be early, there were two Richter’s in each arm so there was no imbalance. I suspect that the Richter’s is not due to the drug, it’s more to do that they’re very poor patients that are going into these studies.
SM: Indeed, possibly even an unmasking of them in fact.
PH: But I guess the BTK mutations particularly demonstrate that if you put real pressure on one molecule there’s going to be a risk of a mutation occurring although it’s very rare to date in follow-up.
JG: So you’re right, so it seems rather rare. Maybe you’d think about suggesting that using single agents aren’t the way to handle relapsed refractory disease patients who often have lots of clonal heterogeneity. There are, of course, other kinase inhibitors that have been reported on here, so do you want to comment on how you see the results with the idelalisib combination versus rituximab that has been presented also?
SM: That’s been presented in the New England Journal of Medicine just recently as well as at ASH last year. There’s a little bit of an update on that but it really hasn’t changed the fundamental outcome for that group of patients to any significant extent except for the slightly longer follow-up. There are a couple of other BTK inhibiting molecules around but broadly they could be said to have fairly comparable outcomes at this point in time. And most of those studies have been on fairly small numbers of patients so far.
JG: And we’re talking also about the usual problem of relatively short follow-up. Do you want to comment at all on the side effect profile, as you see it, between idelalisib and ibrutinib?
PH: I think they’re different and when I say this with different molecules, even targeting the same BTK, for example, because they have off-target effects as well as the on-target effects. So with idelalisib we tend to see the diarrhoea tends to be late and in occasional patients can be very severe and can be colitic and that is something that needs watching and managing so you have to watch and stop the drug early if there’s clearly an issue. There’s a slight concern over whether there’s some pneumonitis with PI3 kinase inhibition, again late. I think the responses in the 116 trial, the randomised trial, are impressive as well and so you have to take these things… you see some very bad groups of patients and they’re getting generally very good responses and we’re seeing some minor reactions. I think with ibrutinib we mentioned that the RESONATE data really mirrors what we’ve been seeing with the phase I/phase II data and going out long term with those drugs, long term two to three years, and there aren’t any major issues that seem to be evolving on the drugs. You have to look at things like immune suppression and the immunoglobulin levels and what’s going to happen if you’re on these drugs for many years because obviously that’s a concern.
JG: The other molecule that’s generating lot of excitement in CLL, of course, is ABT199. So John Seymour updated us at this meeting on the results of the single agent study. So what are you thinking about this molecule and is it worth the hype that the molecule is getting, do you think?
SM: It’s clearly a very interesting molecule and it’s clearly a highly active agent and there’s a range of data that’s emerging. Again, it’s still on relatively small numbers of patients, obviously we’re awaiting the data on the recently closed 17p deleted patient trial and there’s the relapsed refractory trial that’s still got a short way to go. But it’s clearly a very interesting molecule. On that note of potential resistance mechanisms, there’s an abstract by Arnon Kater and Eldering from the Amsterdam group looking at possible mechanisms of resistance to ABT199 and they noted on an in vitro system that CD40 stimulation actually gave resistance to ABT that was actually overcome by dasatinib blocking but not by ibrutinib blocking of the BTK molecule. So I think it’s very interesting to look at the mechanisms that are going to be involved when these drugs come into more wide utilisation.
JG: Andrew Roberts presented, the first time we’ve seen the presentation anywhere, on the ABT in combination with obinutuzumab or GA101. You’re treating patients on that trial right now, what do you think of that combination and what do you think we’re looking for to try to achieve in that combination?
PH: I think combinations with small molecules with antibodies are going to be very important. From the ABT199 the management of tumour lysis has been important and the modifications, we’ve heard some of that data at this meeting, have really shown that we can manage single agent ABT199 by doing a slow gradual increase and watching patients very closely. The anxiety with combining the drug is do you then create more tumour lysis because you’ve primed the cells to apoptose. I think the data from the Andrew Roberts trial suggested that it’s manageable which is, of course, encouraging. There may be some additional tumour lysis that needs to be watched very closely but I guess we’re going to be moving towards combining the B-cell receptors and 199. So the real strength of 199, as well as the fact that we’re seeing really deep remissions at single agent, is that the activity is clearly going to be complementary to the other drugs that you mentioned. So together you’d expect them to be much more efficacious but we have to manage the toxicity.
JG: Now, thinking of combinations of these agents, one concern, particularly for those of us working in managed healthcare systems, are going to be the costs of these agents. They’re very expensive, as marketed within the US at the present time and if we start thinking about putting them in combination are those affordable for our patients within the systems that we have?
PH: I think we have to look at ways to… it’s not just cost, I think what you have to look at is we’ve got patients who are going to become resistant if they’re exposed to potentially long-term drugs and combinations may avoid that resistance. Patients don’t want to be on treatments and coming to see us every three months or more often, they’d rather be, if not cured, free of the disease for a prolonged period of time and then they’d be monitored occasionally, I’m sure, without the toxicity of continuous therapy or potential toxicity. Then, of course, there’s the cost. So I think what we need to be looking at is getting these drugs to the patients who really need it now; the 17p are the patients who have really poor survival and those patients need to benefit now. Then, for the rest of the patients and the patients who will benefit from these therapies, we need to be looking at how can we combine them to get to endpoints that allow us to stop treatment. I think MRD eradication, which is becoming much more robust, is a robust assay, we’re getting better assays for it, would be the endpoint. So we’ve got to look at combining two or three agents together to achieve MRD eradication and then at some point stop the agents so that it’s affordable.
JG: So triple the cost for a defined period being a better way than continuous therapy for many years for these patients.
PH: And that’s why the ABT199 rituximab start to the combination is so important. We have to get to these combinations and do it in a controlled way.
SM: I agree very much with Pete. There’s a cohort of patients that have got early relapse after FCR therapy that have got a very high level of unmet clinical need. It’s very important to get those agents out to those patients. One of the other things that has appeared in the meeting is a number of health economics issues looking at life adjusted quality of life, showing that with rituximab, for example, as well as GA101, that there actually is a positive benefit for that. Those studies with the small molecular inhibitors are probably a bit early to look at in that sense but no doubt that’s what we’ll need to look at as well as the health regulatory authorities.
JG: Thinking of looking ahead, Stephen, you’ve got a big meeting coming up in Down Under next year so we’re all looking forward to IWCLL going south of the equator for the first time ever.
SM: Indeed we have John, yes. That’s correct.
JG: So when’s the meeting?
SM: The meeting is 7th-9th September in 2015, next year in Sydney. The young investigator meeting is going to be on 6th, on the Sunday beforehand, and, as you say, it’s the first time it’s been held outside of North America and Europe and we’re very excited to hold the meeting there for the first time.
JG: And to celebrate it we all have our koala bears, absolutely.
SM: Come and meet our koalas in Sydney.
JG: So what I think I’m hearing from you is a huge amount excitement in the CLL community on the back of these very exciting agents, based not just upon their efficacy but on the fact that we’ve finally got agents which are based upon the biology of the disease. We’re all really excited that we’re hearing more and more updates with each subsequent meeting and we can all look forward to hearing more in the future. So, with that, this is John Gribben reporting for ecancer from EHA in Milan and thank you very much for your attention.
