Expert overview of CLL from ASH 2012
JG: Professor John Gribben – Barts and The London Trust Cancer Centre, UK
PH: Professor Peter Hillman – St James’s University Hospital, Leeds, UK
KR: Professor Kanti Rai – Long Island Jewish Medical Center, New York, USA
JG: Welcome to ecancer; we are here in Atlanta, Georgia for the American Society of Haematology and I’m joined by Professor Peter Hillman and Kanti Rai who, of course, is well known to everyone in the CLL field. So these are exciting times for CLL at this meeting, there’s huge new important biology emerging and really exciting new drugs. So Kanti, for somebody who has been in this field such a long time it must be really exciting to think what used to be available to now be looking at the whole variety of new things we’ve heard in the sessions here today.
KR: That is exactly right, John. The new information in CLL is just astounding. In the last four or five years the field has suddenly taken off and the basis is that at a molecular biology level the discovery and recognition of the B-cell receptor and its signalling pathways have been recognised as one of the most promising themes for addressing the disease almost in the same manner, almost I say, as has been the historic part in chronic myelocytic leukaemia with BCR-ABL strategies. This meeting has been completely overwhelmed, both in the biological part as well as therapeutic part, with the new drugs addressing the B-cell receptor and the activity of these two new drugs. One is a Bruton tyrosine kinase inhibitor which Bruton tyrosine kinase itself helps the CLL cell to proliferate and survive for a long time and this inhibitor will stop that proliferation and its survival. The other one is PI3 kinase inhibitor which also exactly does the same thing, that inhibitor. So we are seeing confirmation of recently discovered observations in the treatment of relapsed refractory patients with CLL who had been previously heavily treated and they had no hope for their future, suddenly they are getting better and have a new lease of life.
JG: I guess one of the exciting features of these new drugs is their ability to overcome one of the major problems we’ve had with chemotherapy, that is the ability to kill cells that are p53 deleted or have mutations of that gene.
PH: Yes. The exciting things, really, are the association with biology and treatment and the fact that these therapies are targeted truly to the path of physiology of CLL. The disease escape mechanisms, the chemotherapy resistance with p53 would be the leading one that evolves in CLL, seems not to interfere with the response to these new agents. So in this meeting, we’ve had in the last twelve months in previous meetings the responses to these agents but we’re now seeing very impressive responses. For example, with ibrutinib in the front line setting there’s over 95% PFS out towards two years now and for the first time combinations with therapies, so better responses with combinations. So I think we’re starting to really explore the activity of these agents.
JG: There’s a great deal of interest, Kanti, probably more so in the US than Europe overall so far, about the so-called chemo-free approach to be able to treat this disease. That of course has real attractions in being able to be thinking about that group of patients who aren’t fit enough for the most effective types of chemotherapy. Do you see, from the data you’re seeing at this meeting, that that approach is a feasible approach we’re going to be seeing in the near future?
KR: I think so. It’s not completely clear at this meeting but there have been a few reports in that direction. As you pointed out, in the United States there is an increasing number of CLL patients who just hate and are mortally afraid of the very idea of chemotherapy. Therefore there are a couple of new, or not so new but still relatively new, drugs which in combination we can tell the patient that this is not classical chemotherapy. For example, the monoclonal antibody against CD20, whether it is rituximab or ofatumumab, in combination with an immune modulating drug such as lenalidomide can do much more than either one of those two agents by itself. That is a non-chemotherapy method of controlling the disease. It doesn’t really control the disease nearly as effectively as the classic chemotherapy but, as you just alluded to, there are some people who have either comorbidities or their age, that they are elderly, or that they’re just in fear of chemotherapy. There our endpoint therapeutic objective becomes different because in the classical sense our therapeutic objective is to try to cure the disease, even recognising that cure is unlikely but we can have an excellent quality of remission and then follow through with more curative approaches. But these are the people for whom they are satisfied with what we call palliation and they are satisfied that we are not giving them chemotherapy.
JG: Now, can I just carry on on that theme because, of course, for the last decade we’ve gone from having clorambucil and you’ve been involved in clinical trials that have moved from almost never getting complete remissions to complete remissions being the goal and, Pete, all the work you’ve done on then getting people into molecular complete remissions. Then along comes a class of drugs that we’re really excited about that are able to control the disease but not really eliminate it. Does that change on a turn of your head your thinking or do you really believe that if we’re going towards a cure that eradication and minimal residual disease still remains the goal of our therapy?
PH: I think we are moving towards much more effective therapies and potentially cure and with the duration of responses we’re seeing with FCR type treatment, if we’re going to compete with that we have to look at the depth of remission as a surrogate endpoint. These new agents that we now have available: ibrutinib, GS-1101, GDC-0199, the PCL2 inhibitor, all look phenomenally effective in CLL. I think we have an advantage, I mean Kanti drew comparison to CML and ibrutinib, but the key difference between CLL and CML is we have with targeting the path of physiology of the disease. So whereas in CML there’s a single target, we have multiple targets which hit the path of physiology in different places. So I suspect that the combination of these agents as we go forward will lead to deeper remissions. And if we’re going to think, and the CML world again is another good comparison, the challenge now twelve or thirteen years on from imatinib is can you stop these agents in people who are doing well? Well if we’re going to do that in CLL we need to have more effective combinations and we need to, I think, have MRD negative patients to have really any realistic chance of stopping the treatment. I think the other way that MRD analysis will be effective is that not only do you eradicate disease but if you get to very low levels of MRD and then you see MRD creeping up on a therapy, it tells you there’s a resistance arriving and then maybe that’s when you should be thinking of altering the therapy or adding two therapies. I think we’re going to evolve trials and develop trials looking at all those aspects of CLL over the next few years.
JG: Do you remain impressed, not just by the response rates to BTK inhibitor, the GS-1101, but also now as we go to each subsequent meeting and we get another follow-up, do you remain impressed by the durability of those responses?
KR: Oh yes, the data that we have seen at this meeting in Atlanta are extremely promising and impressive but no, I would not say that I am completely satisfied because both of these drugs, promising and effective as they are, unless we have had the luxury of going and watching these patients for a few years, it might be premature to claim victory. Not only that, this meeting has also demonstrated that as single agent, each one of these two drugs, ibrutinib and GS-1101, they have activity but if you combine each one of them with some other agent such as a monoclonal anti-CD20 antibody or some chemotherapy, then the quality of response becomes heightened and there my expectation is that the duration of those responses will be longer and eventually the gold standard is are we prolonging, significantly prolonging, the duration of life for these patients who have been previously heavily treated.
PH: I would add to that, we’ve only had these drugs for 2-2½ years so we have to keep that in mind but the excitement is palpable in this meeting particularly. But what’s really intriguing and, I guess, somewhat unexpected is the plateaus we’re seeing in the progression free survival curves and the overall survival curves going out to two years. So there doesn’t seem to be a progressive fall off at this very early stage in the treatment with these agents. Now there must be mechanisms of resistance which will develop but we have other tools in our box now coming along with other therapies that will allow us to probably overcome that resistance. I’m intrigued about combining different biologically active drugs, targeting different parts of the CLL path of physiology, if you like.
JG: There were two things that I was intrigued by in some of the presentations we’ve seen. Of course John Byrd presented the data on one question I’ve been concerned about, that is as we’ve had these patients on longer will we start to see hypergammaglobulinemia? And in fact, what it was showing was that as the patients’ disease responded better, the immunoglobulin levels are going up and not down so we’re not yet seeing that duration of response or that duration of use of the drug is associated with that particular complication. I’d still love to understand quite why that doesn’t happen but I guess what it also shows is that, as we all know, as we get rid of the disease the patient’s immune system seems to recover.
PH: And I guess the other thing, certainly with ibrutinib, is that there are only circulating levels of the drug for an hour in the day and you have 23 hours without drug whereas you have an irreversibly blocked BTK in the tumour cell. So maybe that’s the reason that it allows some sort of recovery.
JG: Sure. The combination of data that Jan Burger presented, particularly in such a high risk patient population. Now, of course, what was missing from that presentation was duration of response; to be fair it’s really just started but very impressive responses and looking to blunt that lymphocytosis. Are your patients concerned as you put them on ibrutinib to see the lymphocyte counts go up, quite often, as high as they do or is that something patients are now used to and expect and it’s not something distressing to them?
KR: It’s not distressing; they are concerned but when they see what we have explained to them, as we understand the mechanisms of these drugs, is that in people who have hugely enlarged lymph nodes under the neck, in the armpits, in the groin and in the abdomen and in the chest, that those nodes dramatically shrink in a matter of a couple of weeks after they start these pills. Then when we explain that those cells are being driven out of those lymph nodes and spleen and bone marrow and where will they go? They have to go into the blood stream. Therefore temporarily there will be an immense increase in those cells; with continued treatment with the drug those high lymphocyte numbers start to go down but it takes weeks and sometimes months and months. But they understand, they are so impressed by the visible benefit that they see in their disease.
PH: I think the challenge, though, I agree and the education of the patients is critical but the challenge for the triallists and the people doing phase III trials is our traditional endpoints are more difficult now. Progression free survival we can accept but assessing response at nine months in the marrow as we would have done with FCR is difficult to compare two arms if FCR is one arm and one of the novel agents is in the other arm. So I think that’s a challenge we just have to accept and right our protocols accordingly.
JG: The other thing, of course, that Jan was presenting is that clearly when the cells leave the lymph nodes into the blood they should be natural targets for antibody killing so obviously a partner for ibrutinib would be rituximab. I was a little bit surprised to see that although Jan was showing a blunting of that lymphocytosis and that many of the patients were coming down, that many of the patients even with rituximab on board are having persistence of lymphocytosis still for quite some periods of time. So he did show and suggested that the combination was leading to faster responses, of course it’s always difficult when you’re talking about single arm studies, but there must be some kind of mechanisms whereby just the constant release of cells from the nodal sites just is overcoming the ability of the antibodies to clear the system.
KR: I agree with you. I was fascinated by those observations. Yes, by and large, most of the patients had blunting of the lymphocytosis but some did not and that raises a very important question, at least in my mind, and that is what is the mechanism that we are very comfortable in thinking that we know the answers. Obviously we don’t because these cells which have been driven out from the organs, they probably have changed their phenotype or other chemokines that they are not nearly as predictably vulnerable to the killing effect of the monoclonal antibody. And that is something which we still have to see. I know that you have been doing lymph node biopsies and blood sampling in various CLL patients but unless we have serially obtained samples of blood lymphocytes, compare them with the organ site lymphocytes and see whether there has been a drastic change. Because CXCR4 expression may be completely different and whether that renders them or maybe any other antigens, whether they will require yet another agent to add to the armamentarium.
PH: I think you have to remember, though, that rituximab as a monotherapy in CLL is not very effective, it adds to chemotherapy and that’s why we use it but if you use it as a monotherapy, as we all have done at some point, you don’t get a lysis of the lymphocyte count, you get a reduction and then usually it will plateau out. So you have one drug which is pushing the lymphocytes into the peripheral blood and then a relatively ineffective monotherapy reducing it. So when the newer antibodies are coming along, and we have ofatumumab is being trialled with ibrutinib in certain trials, GO101 seems to have much more effect on the peripheral lymphocyte count in the early stages from there and so the combination may actually be better with a more effective CD20 antibody than rituximab.
JG: Yes, absolutely. The other exciting drug that is out there on the horizon is the new BCL2 inhibitor which is also looking very impressive in its early clinical trial development. I was reminded of it, of course, because they already have trials open partnering their drug with GO101.
KR: ABT-263 plus GO101…
JG: ABT-199, the new one.
PH: Those trials are just opening, aren’t they, now?
PH: But first of all the 263, ABT-263, which is a BCL2 inhibitor but obviously with a BCL-XL and therefore a thrombocytopenia which is no longer being developed in CLL, the data presented today in combination with rituximab was quite impressive actually. That tells us that 199, which I think is presented tomorrow at the meeting and the abstract shows impressive responses but less mature than ibrutinib, would suggest that we have another very effective agent in terms of responses. And, as I alluded to earlier, I think the attraction is that we know the major issues with the CLL path of physiology are one is the BCL receptor signalling and proliferation due to that and second is a failure for the cells to apoptose. So if you’re going to have a logical combination it would be to take out both of those parts of the path of physiology and you may well actually end up with an extremely effective combination and then adding an effective CD20 antibody to that, you can see why we might be hoping that cure isn’t too far away.
JG: Absolutely. I can see you getting excited about it but having the opportunity to have you both here, you’re both very active in leading clinical trial development. These are some of the most exciting agents we’ve seeing coming along in decades and clearly what we want to do is get these into clinical trials. How are we going to overcome the challenge of multiple agents appearing at the same time; different companies developing those agents and getting those agents into logical clinical trial development? Pete, how are you thinking about trying to get these agents into the way we think of our clinical trial development?
PH: Certainly it’s a good thing.
JG: Yes, it’s a very good thing.
PH: This many toys to play with, if you like, is really important and because they are all different targets so we’re not looking at three different anti-CD20 antibodies; we’re looking at even GS-1101, ibrutinib, GDC199 are all different targets which may well combine well together. We have multiple groups around the world that are doing trials; I think the approaches that one could take are either to add to our current therapies and try and improve the depth of remission but continue the chemotherapy or our group in the UK are favouring a chemotherapy free. We know that first of all patients shouldn’t be treated with chemotherapy, the17p patients, but everybody who treats patients with CLL with FCR-like therapies knows that a quarter of the time, a fifth of the time, patients really don’t tolerate the treatment well. There’s data again presented at the meeting on the concerns of late effects of FCR. So the chemotherapy-free approach is certainly of interest. I think we have to look at surrogates because if you’re looking at young patients with FCR who have a 4.5 - 5 year PFS, it’s very hard to incorporate so many new drugs into our treatment paradigms that quickly, we have to look at relapsed patients where they have poor outcomes and we have to look at logical combinations, really. The different companies is a potential issue but more at this stage where the drugs are going for registration, once they’re registered it gives us more flexibility.
JG: Jan ended his talk by saying that we really need to be thinking about fast-tracking these drugs for development. When agents appear that are obviously this effective, do you believe that the regulatory authorities will appreciate that and move towards faster registration of these agents? Or do you worry that it will take a long time for these agents to really become available?
KR: No, I am optimistic. I feel that the regulatory agencies do recognise, and we have a relatively recent history to assure us that when AIDS drugs came in the time from the first concept of a new drug to actual certification or licensing used to be approximately 5.5 – 6 years and that was shortened to 1.5 years. Similarly when imatinib first came out the pressure and the dramatic evidence of its activity and safety was so impressive that imatinib got approved within two years after its first reported activity. But as you started to suggest, and Pete mentioned too, that we are in that yo-yo of feast or famine and we had a long duration of famine and suddenly we are in a major harvest of excellent promising drugs, suddenly in the last two or three years. It will be a problem because CLL, unlike breast cancer, prostate or lung cancer, is a relatively less frequently seen disease, it’s a relatively rare disease. If you have four or five new excellent promising drugs and the number of patients who are likely to be at risk for entering clinical trials it’s going to be very difficult in order to do a proper reliable disciplined clinical trial. We’ll face that when it comes.
PH: One more thing, I would be very optimistic. I think we have a group of patients which we all accept is an unmet need. The 17p deleted patients and the refractory patients will be why these drugs will be approved very quickly. I think the FDA, for example, looking at MRD as a surrogate endpoint is encouraging that they are looking at trying to fast-track these drugs but we do have to have safety data, we have to have data that’s convincing. So fortunately the drugs are so effective, obviously, the data will be very convincing by the time it’s submitted within eighteen months, two years’ time, whenever.
JG: Of course, talking of effective agents, at ASH this year we’ve got another update on CLL8 continuing to demonstrate the chemoimmunotherapy curves separate further away from FC which is always encouraging and particularly in the higher risk patients, at least in terms of their BLA stage and also, with the exception of the p53 deleted patients, in the classically high risk patients. So a) it’s reassuring that we’re there but we’re almost in a situation at the moment where we’ve got a defined therapy front line for younger fitter patients with FCR regimen and we’ve got these really exciting drugs that are being targeted to another unmet need, that is more elderly patients. Suddenly you’re left with the younger, fitter patients not being offered the agents that we’re all so excited by.
PH: I think what we have to do and what we are doing is getting the front line trials done in the collaborative groups, because they can’t be registration trials if PFS is the endpoint, and getting them done as quickly as possible so that by the time we get the front line licence for the elderly we have data coming through in FCR. Then at least we won’t be… otherwise we’ll end up with patients who are eligible for FCR being treated with a novel agent when we don’t really have that comparison which we need to convince everybody and the regulators that we should be moving over to the novel agents.
KR: I must say that I was encouraged at this meeting in Atlanta that each one of these two new agents, although the major emphasis of current clinical trials has been on previously treated, relapsed, refractory patients, but there are also trials on-going addressing previously untreated patients. So I feel very happy that simultaneously we will develop some evidence of whether we are able to change the natural history of the disease by addressing the previously untreated CLL patients with ibrutinib or GS-1101.
JG: I think you said it very well, Kanti, I think we’ve had a real feast of the science of CLL and the treatment of CLL at this meeting and we just look forward to how this is going forward. So what you’re hearing is that we are all extremely excited by what we have heard at ASH this year; we are all looking forward to the next meeting to see even more mature data appear of these very exciting agents and we’re all very keen to get these agents approved and in our hands so that we’ll be able to take them into the next stage of trial development. So stay with us next year and see what’s next.