SS: Hello, welcome everybody to a series of ecancer.tv. We are here in San Francisco at the ASH meeting and I’m here together with my distinguished colleague, Professor John Gribben from the Barts Cancer Institute in London. My name is Stephan Stilgenbauer and we will cover for you some of the new aspects that are reported at this ASH meeting with a focus now on the novel agents. So, John, we discovered or we discussed in the previous session about 17p complex karyotype, what that means with regard to conventional therapy. There are presentations at this meeting now focussing on particular these subsets of CLL patients with the 17p deletion or difficult to treat with comorbidity, in particular the 1117 study will be presented at this meeting. Do we have a clue what this data could mean for us today and also as a future perspective?
JG: I think, as we all know, the patients with 17p deletions and p53 mutations have been an unmet clinical need: the patients that have been identified that clearly did not respond optimally to conventional chemotherapy for whom we had no real good treatments. And for patients that were young enough the guidelines suggested that even in first remission these patients should be considered allogeneic transplant. Now an allogeneic transplant is a very blunt tool to treat these patients so finding now that we have three agents, two of which are approved and one in clinical trial, namely ibrutinib, idelalisib and ABT-199, all showing very good activity in these set groups of patients is hugely exciting in terms of what we think about for these patients. Now, of course, the two agents that are approved have been approved in Europe, not only in the setting of relapsed refractory but also for 17p deleted, p53 mutated patients. So that means that right here and now we have much more effective therapies for our patients with these abnormalities. What these meetings bring to us is further follow up on these groups of patients to really give us a much better insight into what’s the type of duration of response; hat’s the toxicity profile that we see with these agents. For us, still an issue becomes are these a very good way to get patients into good responses and should patients still consider transplant, or are these a very good alternative treatment to transplant. What we’re seeing is follow-up data that helps us to make those determinations.
You raised particularly the RESONATE 17p trial which Susan O’Brien presented here showing that in that previously difficult to treat group of patients, these 17p deleted patients, not just front-line but relapsed showing very high response rates, much higher response rates than anything we’ve ever seen with conventional chemotherapy before. And showing, with further follow-up, that the data maturing, showing that we’re seeing 79% progression free survival on median follow-up. Really encouraging results strongly suggesting to us that in this very difficult to treat patient population that we’ve got very effective agents to build on going forward.
SS: So from your opinion you would think that this data confirms the way these agents are licensed, in particular from that trial for ibrutinib, that this is probably one of the best treatment options available for patients with the 17p deletion?
JG: I think these agents are the best treatment. They’re vastly superior to therapies that we’ve had before and producing comparable and better results with very much less toxicity than allogenic stem cell transplants. For me the issue remains what’s the durability of the responses that we’re going to see. We knew before we came to this meeting from the data we’d seen in previous presentations and from the published data, we knew that the 17p deleted patients were responding well to these agents. What I’m looking to get out of these meetings is each time we come to another ASH, another EHA, another ASH is looking at the durability of the responses. What we are indeed seeing is that there are groups of patients who are continuing to remain in remission long-term with these types of agents. Like everything else the big question now is trying to identify who are the patients who are destined to relapse, who are those patients who are destined to have very long remissions and how can we start to study who those patients are. Now we haven’t seen much in the way of data relating to that at these meetings but what we are seeing, however, is more mature data than we’ve seen before.
SS: Absolutely. The other agent that you’ve alluded to briefly already is idelalisib and we have another trial being presented here on actually a randomised comparison but also a sub-group analysis from that trial focussing also on the 17p patients, can you comment on that?
JG: Sure. Obviously this was the idelalisib plus rituximab versus rituximab plus placebo trial and we’ve already seen that data published in the New England Journal. What this analysis here focussed on are the sub-group of patients who had 17p deletions, which was quite a sizeable proportion of patients in the study for two reasons: one, those patients make up a good proportion of patients, as you’ve published before, of relapsed refractory patients. But also as these agents were demonstrating efficacy these were the types of patients that were often being referred into the trial, so these trials were enriched for patients with 17p. What that means is there’s enough patients within these for such subset analyses to be performed. What the data clearly demonstrated from the idelalisib rituximab data was that we’re seeing no difference in progression free survival between those patients who do or do not have abnormalities in the p53 pathway, be it from deletions or mutations. That’s telling us that these agents are clearly able to overcome the poor prognostic feature associated with p53 abnormalities. That’s something that you and I a few years ago would have thought was an inconceivable advance from where we were before these agents became available.
SS: Absolutely. You also refer to that there’s a third agent around targeting Bcl2 so when you compare this to ibrutinib and idelalisib where do you see the pros and cons or can you weigh it in some perspective? Also with regard to 17p possibly.
JG: Well the obvious thing to say is we’re talking about two approved agent versus one agent which is very much still in clinical trial development. All of us have been excited to see the response rates that we do see with ABT-199 and we’re seeing data at this meeting, both alone and in combination with anti-CD20 monoclonal antibodies. There are major problems in terms of how we learn to handle this drug. My own personal view is that tumour lysis syndrome is a problem that is a good problem to have because it tells us we’ve got an agent which is very effective in the treatment of CLL. The data again clearly demonstrate to us that it’s also very effective in patients with p53 abnormalities. I’m excited that we have an agent that I think tells us not only a huge amount about the biology of CLL, because I would never have predicted that CLL would have been so addicted to Bcl2 that removal of Bcl2 alone would have led to such responses and I wouldn’t have predicted either that we’d see such good and such durable responses in the 17p deletion groups not being different from other groups. So that, for me, is data that I couldn’t necessarily have predicted. We have to also be aware that we’re seeing much more mature data with idelalisib and ibrutinib than we’re seeing with ABT-199 which is further behind in its clinical trial development. So in terms of where would we put it right now in terms of which agent would you use, well we’ve got two approved agents and we’ve got one agent in clinical trials. You and I are both taking part in enrolling patients onto clinical trials with ABT-199 and if I didn’t think the agent looked a very attractive one I wouldn’t be offering those sorts of trials to my patients to take part in. So I’m very excited about the potential that this agent might have of thinking about a defined duration of therapy.
Now, I’m saying that, we didn’t see any data at this meeting that tells us that we can give a defined duration of therapy but I think we’re seeing perhaps very deep responses occurring with ABT-199 in a very different way than we see with ibrutinib and idelalisib. So nothing for my mind that’s practice changing but I think it’s giving us a great deal of thought in terms of how are we going to use these agents going forward.
SS: Now you mentioned that among young patients, even in the front-line treatment setting, CLL patients with the 17p deletion were considered ultra-high risk and you considered, even in the first-line treatment setting, an allogenic transplant in these patients. You are well known to be among the pioneers of transplantation in lymphoid malignancies so would you think that these agents put you out of a job?
JG: I’ve always said that I hope that a better treatment than an allogeneic transplant becomes available for our patients. Even with advances in doing transplantation and even with reduced intensity conditioning regimens which are the ones largely used in CLL, I’d much rather treat my patients in any other way than an allogeneic stem cell transplant. What I’m looking for in my patients is that they achieve prolongation of their life and very good quality of life. The question remains should we use any of these agents to get our patients into remission and then still consider them for transplant. The guidelines still say that and brand new guidelines were just recently published online in Blood where you see that the consensus statement on whether we should use these had led to no consensus whatsoever because there isn’t yet sufficient data for us to make changes. Basically it was most interesting that among those panels some more conventional transplanters were more willing to be considering transplantation should be held off whereas some of the people who are more conventionally thinking about therapies were the ones who were thinking that transplant should still be offered.
The guidelines clearly still say that for patients with 17p deletions that transplant should be considered for those patients in whom a donor can be found and who are eligible patients for transplant. But what you’re hearing is that we’re having discussions within the community about what exactly we should do. In an era where we only had one agent if the patients failed that agent and progressed rapidly you may miss the window of opportunity to transplant them but now we could potentially be thinking about sequentially moving from one regimen to another. So for me this is a highly contentious issue and why I want to see the data much more mature than before in terms of trying to make those decisions. It is clear, irrespective of how good the data that Susan O’Brien showed with ibrutinib, that patients with 17p deletions still appear to be doing less well with ibrutinib than those who do not have 17p deletions. Although in the idelalisib setting we saw comparable outcomes for both, the toxicity of that agent may in fact mean that we should be thinking about whether or not we need to be having these long-term. So these remain unresolved issues.
SS: Right. You alluded to the fact already that there is at least one population, namely the 17p, where probably we need much more research and clinical trials are needed. What is your vision? How do you, when you look forward, see these agents being further developed? Should we look into combinations, should we look into particular populations? What is your view on that?
JG: I think everyone’s interested in will a combination of these novel agents get us from where we are now, that is very, very good responses, and let’s not forget that these are much better responses than we’ve ever seen with anything before. And getting there but patients still be talking about continuous therapy versus can we get to a point where we have a defined therapy. What I know that my patients want is to be cured of their disease. I think moving towards cure rather than long-term control remains at least my goal for the present time. I’ll take long-term control over no control. So I think potentially combinations of these agents may indeed be the way that we have to go forward. What’s very clear is that our health economies are not going to able to absorb combinations of these agents at these costs very long term so unless we can find a way to giving a defined period of therapies, I can’t see ways in which we can realistically look to combine these types of therapies indefinitely.
SS: Apart, maybe, from certain subsets of patients like the ones with the 17p deletion where already we know that with single agents we don’t really solve the problem and maybe also combinations would lead to finite treatment durations.
JG: You’re absolutely correct and that’s where the scientific analysis of identifying who are the subsets of patients, is it indeed just 17p or, as we heard from data from MD Anderson, is it more complex karyotypes or, as we will learn from next generation sequencing and there are posters at this meeting that have been looking at many of those issues also, that maybe the advances in science that we have will enable us to identify who are the groups of patients that may particularly need therapy in a different way. I do think that not just in CLL but in virtually all the diseases we’re thinking about, the idea that one treatment is the right treatment for all patients with a particular disease is probably soon going be over and we’re going to really much more tailor the individual therapy to the underlying biological basis of the disease. That remains still a clinical trial question but that’s how I see the field going forward.
SS: John, thank you very much. I think we could go on for hours and what we discussed really underlines the great progress that has been made with regard to chemotherapy as a front-line, as still the standard front-line treatment, but also with regard to the novel agents and a better biological understanding of the disease that actually forms the basis for these new treatment approaches. Thank you again very much, I hope our viewers enjoyed the programme. I think it’s exciting times for us as researchers but most importantly very, very good times for the patients and with this very hopeful and very nice outlook we’ll conclude the session. Thank you very much.
JG: Thank you.
