Dr George Follows and Professor Peter Hillmen 

GF: Hello, my name is George Follows, I’m a consultant haematologist in Cambridge. I run the lymphoma CLL programme and chair the UK CLL forum. I’m here in Edinburgh at the BSH meeting and I’m delighted to be able to talk with my colleague, Pete Hillmen, who is a consultant haematologist in Leeds and chairs the UK CLL trials programme. So, Peter, it’s been a great meeting. We’ve had the parallel sessions and the lymphoproliferative session which, I must say, again dominated by CLL this year.
PH: Of course.
GF: Which we were seeing some updated data on two of the largest randomised trials in relapsed CLL. That led us into the UK CLL forum session which, again, the BSH has allowed the forum to have a session, which is tremendously exciting. So what would you say grabbed you from this morning’s session with the update on the relapsed data?
PH: As you mentioned, it’s a very exciting time for CLL and it is dominating a lot of the lymphoproliferative sessions. The two major trials which we heard updates on, which we’re getting familiar with now, the first one was looking at idelalisib and rituximab. So the 116 trial, the randomised phase III trial in relapsed refractory disease in patients who really aren’t eligible for chemotherapy, which has shown really impressive improvements in progression free survival; even at the late follow when patients have crossed over we’re seeing a 75% improvement in progression free survival for the patients treated with idela plus rituximab compared to the placebo rituximab patients and a 66% improvement in overall survival. So really a dramatic efficacy. In that trial, and the other supporting trials, we’re seeing acceptable toxicity. These drugs aren’t without their side effects but we see some liver enzyme abnormalities which are reversible and they aren’t a problem, and we see some diarrhoea which is slightly more of a concern for a small proportion of the patients and needs to be watched for and managed more appropriately.
GF: It’s interesting, the idela trial, because gosh, some of those patients were really quite sick going in. I’m thinking of some of the patients I recruited into that trial and the data shows us, doesn’t it, that in terms of performance status at trial entry. Do you have views on that?
PH: Yes, they were certainly the most… a trial with the most ill patients that we’ve really put into CLL trials. There was no cut-off; there were performance status 3 patients there, about a third of patients had grade 3/4 cytopenia, some of them being transfused. So they really were a difficult group of patients to treat and an average age of 71 so they were representative of the CLL population really.
GF: Yes, multiply treated relapsed refractory patients. I think with the toxicity we’re getting a better handle on how to deal with that, aren’t we? The percentage is relatively small but it’s like dealing with the altered liver enzymes or the diarrhoea and actually having your strategy in place so your patients are educated and your teams are educated.
PH: Yes, it’s just being aware, particularly of diarrhoea and pneumonitis as things you need to look at, because they tend to happen a bit later on in the treatment so patients have settled down, they’ve responded well and then they develop the diarrhoea. So they need to be aware to report that to you because it’s manageable if you can catch it early enough. Of course, this is an elderly group of patients so diarrhoea can cause other problems – dehydration etc. The other trial which I think was updated, which Claire Dearden updated at the meeting, was the RESONATE trial of ibrutinib which compared ibrutinib to ofatumumab. Again, very impressive improvements in progression free and overall survival in that trial compared to ofatumumab; again with a crossover from the ofatumumab arm to the ibrutinib arm for the majority of patients. But that’s given as a single agent, an impressive drug as we’re aware. Slightly different side effect profile with some bruising and a bit of bleeding the most obvious problems. If you compare the two trials, because of the eligibility of the trial and the patients going in, the RESONATE patients, the ibrutinib patients, were slightly younger and had slightly better marrow function going into the trial. So it’s very hard to compare the two trials directly.
GF: I think we’re blessed, though, with suddenly two agents that really are showing remarkable efficacy. I guess you’ve experienced the same, that patients come in and you lead them along, ‘Do you prefer this or chemotherapy?’ and we always get the same answer.
PH: I think that’s the excitement and part of the excitement is also the next generation of these drugs that are coming along, the PI3 kinase gamma delta inhibitors, alpha inhibitors which you presented.
GF: I was able to update some of the Bayer data which is quite an inclusive trial; that was in a parallel session. It included some CLL, indolent lymphoma, aggressive lymphoma, showing efficacy. It just illustrates this point, doesn’t it, that so many different targeted inhibitors are coming into the marketplace, sorry, the developmental space, that we as triallists are going to have to think quite imaginatively about how we fit these things together because I know that’s a topic that’s quite dear to your heart, isn’t it Peter?
PH: Yes, the session, the UK CLL forum session, which we’ve just come from where there were three speakers, we saw slightly further into the future with the PD1/PDL1 inhibitors, the immune checkpoint inhibitors which are exciting across cancer. But also CLL expresses these molecules at high levels and therefore it’s likely to be very sensitive to them, although we don’t have any clinical data yet. Then the CAR T-cells which, of course, has been excitement for the last few years but are quite a challenge to implement really. There’s a programme at UCL, here in London, that’s looking at doing that in CLL amongst other diseases, although that’s a little bit off getting there. And then I summarised our UK CLL trials approach which I think what we’re going to have to look at is how do we move this wide range of therapies logically to combine them, probably with each other or with chemotherapies to actually moving toward cure. It isn’t unrealistic to expect that we can challenge the paradigm that this is an incurable difficult to treat disease and move towards MRD negative remissions and potentially certainly coming off therapy of these novel agents and potentially moving towards curative strategies.
GF: Yes, tremendously exciting times. I was struck by your discussion about how encouraging the regulators to look at different endpoints because, quite a telling point, that you showed that despite very active CLL trials groups at the British, what, three randomised trials and the German’s three randomised trials over 15 years. Clearly with such a raft of new, potentially efficacious, drugs we’ve got to come up with new trial designs that can address this issue.
PH: We have to be a lot more nimble on our feet, really, and we have to have our own phase II data, combination data, as we’re getting through the LLR TAP programme in the UK so we can do some more studies collecting a lot of biological data to understand really how these drugs work, how they combine with each other, what’s the logical combination, and then move them rapidly into phase III. We can’t be opening a phase III trial, waiting for seven years for the results and then negotiating for the next one, we have to be getting through these novel combinations really rapidly. The FDA is looking at an adaptive trial design and across cancer that’s where were moving to, to have a basket trial that you keep adding new therapies into and don’t close down this big machinery that we create for a phase III trial.
GF: Yes, they’re tremendously exciting. So if I had to get you to crystal ball, Pete, if you were looking to ASH, looking at trials that you’re most excited about seeing reported?
PH: I think we’re moving now to the combinations. So we saw at last ASH the first combination of Venetoclax, ABT-199, plus rituximab and seeing MRD negative remissions. I think we’re moving now rapidly to the second generation CD20 antibodies in combination with small molecules. We’re going to be doing novel, novel agents combined. At ASH we’ll see the first front line randomised trial with a B-cell receptor antagonist, RESONATE-2 will probably read out then, I suspect. I think everyone is looking forward to that because these drugs are going to be more effective the earlier we use them in the therapy of patients. Now there are a lot more challenges because we’ve got very effective therapies, if you look at FCR we’re seeing in the UK trials 70% CR rates, 50% MRD negative rates, and many patients off treatment for ten years. We’re replacing that at the moment with continuous therapy with very unknown toxicity or efficacy going out beyond three or four years. So we have to move the combinations. I think everyone wants to get away from chemotherapy but we mustn’t throw it away until we’ve actually proven what we’re replacing it with is actually better.
GF: Yes, and I guess if Anna Schuh was here, our good colleague from Oxford, she’d be telling us that this is why we need to personalise the science behind CLL. Because if we can understand the difference between individuals in terms of their genomic mutational profile, their signalling pathway dependency, we would actually be pushing patients down the right therapeutic pathways from early on.
PH: Absolutely. Resistance, for example, we need to understand resistance to these molecules. One of the huge advantages for CLL is that we have the cells so we can give a drug and then one hour, four hours later we can collect the cells and see what’s happening to them. There are very few of our other malignancies that we can do that. So I think that and the fact that most of the drugs seem to be effective in the disease mean that CLL is likely to be at the forefront of the curative strategy for cancer because we can learn so much about how our therapies work immediately and in long-term.
GF: You actually allowed us a little snippet of data that I presume you’re presenting at EHA looking at that very close sampling of patients just starting some of these novel therapies.
PH: Yes, that’s right.
GF: I felt sorry for your lab chaps because you’re all struggling with four hours, eight hours, twelve hours, sixteen hours, obviously working through the night on your samples. Excellent, Peter. Well, I think that really summarises for us what is the most interesting from the CLL perspective at BSH but very exciting times, aren’t there? So I think we’ll sign off at this point and do keep an eye on the CLL forum and the meetings. Our next meeting is in London on 1st October.