BSH 2014
Rituximab versus idelalisib in refractory CLL
Prof John Gribben - Queen Mary University London, London, UK
Prof Peter Hillmen - St James’ University Hospital, Leeds, UK
JG: Welcome to ecancer. I’m John Gribben from Bart’s Cancer Institute in London. We’re here in Birmingham at the British Society of Haematology meeting 2014. I’m joined by my esteemed colleague, Professor Hillmen, who leads the CLL study group in the UK. So, Pete, an exciting time for CLL in terms of the emerging numbers of agents that are appearing. Maybe we just start by thinking about how we start thinking about these novel agents in the setting of what our current practice is.
PH: Well we have, as you say, an increasing number of novel agents with different targets. With the approval, probably, of two of them this year and hopefully the funding approved for the drugs, we’re going to start using them in the relapsed refractory setting, the patients where we have no effective therapies or the therapies we have are really rather toxic. These therapies are clearly more effective, we know that from one published randomised trial and another one which we’ll hear about in the next few months, and are much better tolerated and much more effective than the conventional therapy. So I think initially we’ll be starting to look at the relapsed refractory patients, the 17p deleted patients, and then moving on with our trials to further front line in combination with other agents.
JG: One of the exciting things about many of these novel agents is the fact, as you’ve already mentioned, that they look as if they’re effective in these 17p deleted patients that have clearly been an unmet clinical need to date and are a really difficult group to treat. Of course for younger patients you’d think about things for transplant but for many elderly patients there were really no particularly effective therapies to manage this disease. I think that’s one of the exciting things about these agents.
PH: Yes, I agree. And the toxicity is significant with the therapies we’re using, the conventional Campath based therapies or if people use high dose steroids and chemotherapy, and the duration of remission is so short that the median survival, certainly in relapsed patients, is a year or less. So we’re really making major inroads into those troupes of patients.
JG: You mentioned, of course, there was very exciting phase I and phase II data that came out but now there’s a randomised clinical trial looking at one of those agents, idelalisib, which one would expect, on the results of the clinical trials and the ease with which it went through the US regulatory authorities, that we should see approval in the EMEA within this next year, one would expect.
PH: Yes, I think so.
JG: So, of course, in that trial patients were randomised, relapsed refractory patients were randomised to receive either rituximab and placebo or rituximab plus idelalisib. Now, of course, there was a fair bit of criticism in Europe for the choice of the control arm in that study. What do you think about it?
PH: I think first of all the patients entering that trial were the worst patients we’ve put in clinical trials in my experience of doing trials. We’ve had no randomised trials for patients who… really, some of the patients were profoundly cytopenic, unfit for chemotherapy, transfusion dependent even, which usually would have been excluded from our previous studies. If the control arm, as you mentioned, which was rituximab monotherapy isn’t a therapy we would have used in the UK or in Europe generally, although it is used in other parts of the world, but the outcome of that group of patients, the control arm, in terms of progression free survival is very similar to the treatments we have for those refractory patients. So if you look at ofatumumab or chemotherapy or Campath a PFS of around six months is what we would have expected.
JG: So has that made you think again? I mean, a lot of controversy about the way the Americans have been using rituximab. It does have some efficacy in that control arm.
PH: There are certainly some nodal responses but most patients don’t have a significant response. There are some lymphocyte responses but the duration of the response is very small, only less than 15% of patients actually achieve an objective response in the control arm of the trial. So I don’t think it’s a reason to use rituximab in that setting, no.
JG: Sure, OK. Now, you already talked about that this was a very high risk patient population, so elderly, poor creatinine clearance. So these were not patients in whom we really had other good options, other than enrolment in clinical trials.
PH: No. I think that’s right and it was a placebo controlled trial which, for CLL, is very unusual. I can’t really remember one with a crossover, but even the crossover was blinded. I was an investigator on the trial, it was a really quite difficult study to perform because we didn’t know if the patient was on active therapy, we needed a confirmed progression by an independent review committee to allow them to crossover which meant patients stayed on the control arm for longer than we felt we wanted to keep some of the patients on. So it was a very pure trial in terms of the design but clinically quite difficult to manage.
JG: I think there are a number of notable issues on this trial. One, the speed with which, even for this high risk patient population, the trial was able to be completed, just over a year of accrual. Then, of course, the results showing very impressive results. So would you like to just comment on the results of the trial?
PH: As you say, the results were very impressive, over 80% of patients responded and the patients going into the trial were very heavily pre-treated, almost half of them had 17p deletion so they were the worst patients we could put into trials. So 80% plus responded, there was a very significant difference in progression free survival which was the primary endpoint and even in overall survival, at a very short interim analysis, there was a significant difference.
JG: Yes, I was going to come back and talk to you about that. Given that there was a crossover design, that is the patients who… well, as you’ve already said, you didn’t know which, but the patients who were getting rituximab plus placebo at progression were allowed crossover. So I think it came as a surprise to many of us to see in such a short follow-up period an overall survival advantage in this trial.
PH: I think so, but I think it reflects the type of patients going into the studies. One of the reasons, alluding to the previous question about the control arm, we don’t have a standard of care for those patients and the outcome is really very dismal for patients who are unfit for chemotherapy and have failed several lines of treatment. I think that reflects the PFS being very poor and patients not surviving after they’ve failed single agent rituximab.
JG: We’ve had a number of trials recently, having had none for decades, where we’ve seen overall survival of one arm compared to another. Would you agree with me that this is really an indication that we shouldn’t, perhaps, be starting gently and ramping up with therapies but using our most effective therapies first?
PH: I’m sure that’s right, we obviously need to do the trials to prove that these are effective. So if one considers the completely opposite type of patients, the patients in front line who are fit for FCR, our FCR based therapies are very effective. We see almost 100% responses, 97% in our latest trials if you exclude the 17p, 70% CR rate, over 50% MRD negative rate and very durable remissions. So it’s very important we don’t throw away the advances we’ve made over the last ten years in the treatment of CLL because we don’t know what the long-term effects of these agents are. So it’s very important we do appropriate clinical trials to show that these targeted treatments are better in the long term. I think what we’re seeing is that we’re actually now understanding more about the pathophysiology of the disease and we’re actually targeting if not the molecular lesion, as we would in CML, but the very critical pathways in the pathophysiology of the disease. If you look at that in targeted treatments generally you see rapid responses, as we’re seeing, and they presumably are effective than the conventional less sophisticated treatments.
JG: So just to go into that in a little more detail, idelalisib is a PI3 kinase delta inhibitor so where exactly is that in the CLL pathway in terms of what you’re talking about, the pathogenesis of the disease?
PH: Yes, so I think we have two, at least two, interesting pathways which we’re targeting. The B-cell receptor signalling is critical for probably most patients, if not all patients, with CLL. Certainly the poor risk patients are clearly dependent on signalling through the B-cell receptor. The PI3 kinase delta is part of the transfer, the transmission, of the signal from the B-cell receptor into the nucleus which leads to the proliferation and probably some of the other functions such as the homing of CLL cells. So it lies fairly approximately in that pathway. The delta isoform of PI3 kinase is reasonably specific for the B-cells and basophils and haemopoietic lineages. Idelalisib is a very highly specific delta isoform inhibitor.
JG: Now that you’ve, of course, had experience of treating patients, when this drug becomes available and people start thinking, what are the features that you saw from your own experience and from the patients on the trials in terms of what you should look for – the side effects and things like the lymphocytosis early after treatment?
PH: Yes, I think it’s very predictable. There’s what appears to be a shift of disease from the tissue compartment into the peripheral blood. So with all the B-cell receptor antagonists we see a lymphocytosis. Idelalisib is used with rituximab and that seems to blunt that lymphocytosis so it’s really not a major issue with idelalisib. If you look at the trial you can see that, as I said, 80% had a partial response so therefore didn’t have a lymphocytosis at any… it was only three months into treatment so that it’s very short-lived when used with an antibody. The follow-up in the randomised trial is still relatively short so we need to watch this space in terms of long-term toxicity because from the phase I and phase II trials there is a slight signal for colitis in a small number of patients with idelalisib at the six month and beyond time and that, although not usually life threatening, can mean you can’t give the treatments once it is controlled. That happened in a small percentage of patients from the phase I/phase II trials. Then there’s a slight concern over potential pneumonitis, which obviously pneumonia is a feature of CLL particularly in the refractory setting, but there does seem to be a very small proportion of patients who may have pneumonitic type symptoms late out and that needs to be watched as well. Having said that, the treatment is very well tolerated and the vast majority of patients feel very well very soon after starting the treatment and, in my experience, the tolerability is very durable over a period of time.
JG: Now, you mentioned the late colitis but there is some degree of GI upset that’s reported from the trial. Was that in your experience something that was a major problem for the patients or something you really had more to elicit from the patients when their follow-up studies?
PH: Yes, I think it hasn’t been a clinical problem for idelalisib. This group of patients, actually, is quite difficult to elicit symptoms from because the last thing that they want to do is stop a therapy that they’re feeling better on. So there’s always an element of, ‘Well, we’ll just deal with it.’ But it does seem to be rarer with idelalisib than ibrutinib in terms of a short-term loose motions rather than diarrhoea and usually within a month or two that symptom settles down. So it’s very controllable.
JG: You mentioned this was a very heavily pre-treated group of patients, was there much in the way of hematologic toxicity that you saw?
PH: In fact, many of the patients went into the trial with grade 3/4 cytopenias and there’s relatively limited haematological toxicity. It’s not like a chemotherapy, we do see the occasional patient with neutropenia or other issues but they’re manageable generally and don’t usually lead to the cessation of therapy.
JG: You’ve already mentioned these drugs are going to be approved soon for relapsed refractory patients. Where are we going from here in terms of thinking about bringing these drugs more into front line therapies?
PH: That’s a very good point. The obvious place to look at these treatments is either to replace chemotherapy in those patients where there’s an anxiety over giving chemotherapy and, of course, many of our patients are anxious about chemotherapy to start with, even without any knowledge of the treatment. We do know that some therapies are probably associated with long term side effects. Or to add to chemotherapy to try and improve the remission rates. We know that high response rates, more MRD eradication, leads to much more prolonged responses. So we're looking at bringing these treatments immediately into front line trials and we have a planned trial in the UK which we’re modifying to add to chemo-immunotherapy with idelalisib. I think then the next step will be looking at combinations of novel therapies, so one of the issues with most of these treatments is they change the paradigm of treatment from a block of treatment that we stop after six or maybe up to twelve months to a continuous therapy which has several drawbacks. If we can combine either novel therapies with conventional therapies or novel therapies in a logical way together the hope would be we’d be able to stop the treatment because we had much better responses.
JG: One of the issues is going to be, of course, in the US these drugs are being sold at very expensive levels and the question is that in nationalised health systems like our own how are we going to be able to afford it. What you’re alluding to is that it may be better to have more expensive combinations of drugs for a defined period than a single less effective drug, potentially, over a very long period of time. Is that the way that you see this probably going forward?
PH: I think that’s right. If you look at the other diseases where we have multiple therapies, whether they be chemotherapies or in some infectious diseases, targeted treatments, they’re better in a genetic system to hit different genes so the disease can’t escape from control. It’s not just a pharmo-economic issue, I think patients prefer not to be dependent on a therapy continuously. We have to be concerned over the medium to long term of the potential evolution of resistance to these agents and therefore not being on them in the long term probably reduces the risk of resistance. And, of course, there’s the obvious pharmo-economic issues as well. So I think, certainly in the UK and probably in the other nationalised health systems, we’re going to initially be looking at selected patients, the patients who are really in that unmet need category, the 17p refractory patients. We’re going to have to look at those and then generating the evidence in the patients where we do have treatment options to show that, first of all, they’re better and how we should best use the therapies.
JG: We started off by talking about the FCR, still the standard of care for our up front patients. Most of these trials of these novel agents have actually targeted the non-FCR patient population. Of course a lot of these younger, fitter patients are suddenly finding that they’re not getting access to these agents. What’s it going to take for us to think about not offering FCR to a patient but offering these agents and what advice would you give a patient who tells you he doesn’t want chemotherapy who would be otherwise fit for it who comes asking for these types of therapies?
PH: I think that’s a very difficult and very pertinent issue that we’re seeing with many of our patients. We are moving also to understanding in a much more personalised way an individual patient’s disease and that may well lead us to the most appropriate therapy. So, for example, if you look at the FCR data, and the longest follow-up in that series of patients is from the MD Anderson, but we have now several years of follow-up, the very profound and prolonged remissions are in the VH mutated patients whereas the early data in most of the B-cell receptor antagonists suggests that the unmutated patients respond more quickly and in fact the mutated patients respond more slowly. So you could almost see that if you had a mutated disease needing therapy that FCR, there’s a small risk long term, but you’re probably going to get a ten year plus remission and that’s probably acceptable whereas the unmutated patients you could look at it and say, ‘Well, actually, you may get five years of remission and that’s not adequate,’ and therefore novel therapies are more appropriate. 17p, of course, we would take out and say that we don’t have an effective therapy front line and we need to look at these agents in that context. The other pathway that is now being targeted in CLL is the BCL2 apoptotic pathway and the early results from ABT-199 or GDC-199, which target BCL2, are really very impressive as well without the lymphocytosis. So that may lead to a logical combination approach. There are obviously issues of safety and tolerability of single agent and combinations but I’d be optimistic we may be moving towards the period where we can give a short course of both those therapies together. At the moment that’s not an option for the patients outside trials.
JG: But you see us moving towards a much more targeted approach based upon the specific genetics of the features of a patient’s own CLL and perhaps a one approach fits all is going to be the old way of doing it. But it’s very exciting that we’ve got this number of new agents coming in, to be able to start having that approach.
PH: Yes, I think that’s right. The other element of treating people with FCR versus single agent ibrutinib or single agent idelalisib now is that if in five years’ time, or whenever we have defined the optimal way of using these agents together, we’re going to be using two or three agents together to target a patient and get very deep remissions what you probably don’t want to be is resistant to one of the agents. So if you’re actually going to get a durable remission with chemo-immunotherapy you’re almost better to get that and when the disease comes back, which we have to assume it will do at some point, it’s likely to be five or more years downline, and we will have a better idea of how to use them and you won’t be refractory to one of what will probably be a key element of treatment. I have to say when I’ve discussed that with patients and we have these discussions it doesn’t always hold a lot of water but logically that’s a sensible approach.
JG: So an exciting time in CLL, yes?
PH: I think so.
JG: OK, in that case here we are at the BSH. We’re hearing at this meeting, as we’ve heard at many of the other haematology meetings recently, very exciting time for CLL in terms of both our understanding of the pathophysiology of the disease, the new agents which are emerging, targeting those therapies and a new paradigm opening for our patients.
