ASH 2015

ASH 2015: Ibrutinib as first-line treatment for chronic lymphocytic leukaemia

Prof John Gribben - Queen Mary University of London and Barts Cancer Institute, London, UK
Prof Stephan Stilgenbauer - University of Ulm, Ulm, Germany

JG: Hello, I’m John Gribben from Barts Cancer Institute in London. We’re at ASH 2015 in very sunny Orlando and I’m joined by my good friend, Professor Stephan Stilgenbauer from the University of Ulm in Germany. So Stephan, lots of news here, of course, as usual; a lot, of course, about ibrutinib, I think we all agree a very exciting advance in terms of the treatment for CLL. What I’d like to do is spend a little bit of time today thinking about who are the right patients when we’re considering ibrutinib, when a patient should consider going on the drug and what they should think about going on to the drug rather than focus on, this session particularly, about some of the new things that are appearing. But, of course, we are seeing lots more data appear, lots more mature data and lots of new clinical trial information. So, for you, what is the major advance that we see in terms of having ibrutinib as a treatment for our patients with CLL?

SS: John, traditionally ibrutinib has been licensed for the relapsed refractory population, for the high risk population with the 17p deletion or TP53 mutation and rightly so because these are the patients traditionally that with chemoimmunotherapy had very, very poor outcome and for whom ibrutinib really was a breakthrough and still is a breakthrough. Now, as you say, we are moving more and more to earlier treatment lines and at this meeting data will be presented, actually, from the front line trial, RESONATE-2, for patients over the age of 65. Again, everybody knows from the abstract already that the data will be really overwhelmingly positive.

JG: Now we saw, of course, not the front line data but data presented here before from the original RESONATE study suggesting a better outcome for people treated earlier in the disease. Now there are a lot of people out there believing that maybe we should keep this drug until last, last resort, is that your view on how we should be using this drug?

SS: This comes traditionally from the licensing trials where it was used in end stage patients or the ones who really were refractory to all other available therapies. As you say, the original RESONATE study already indicates that patients with fewer prior lines had a better outcome so with indirect evidence, so to say, supporting earlier use and if the evidence now really from phase III trials in the front line treatment shows that the outcome of these patients is really so remarkably good this provides further argument for earlier use.

JG: Sure. Now, some patients are a little bit alarmed by some of the early signals coming out of those studies. The first one, of course, is when these studies were first being done there was the signal that maybe that we’re seeing quite a lot of Richter's transformations in those patients. Now, clearly we were, is it your view that in some way these drugs are causing Richter’s transformation?

SS: Well, as you say, there was quite an incidence of Richter’s transformation in the ibrutinib arm or in phase II single arm studies of ibrutinib causing this, and rightly so, this concern. Biologically, as you know from a biological disease perspective there’s no reason to think why this drug should induce Richter’s transformation. I think a good piece of evidence comes from randomised comparisons where you can compare both arms and actually with all caveats the incidence of Richter’s transformation is somewhat similar in both arms although you have to remember that in the ibrutinib arm the patients simply have been living longer. In these very high risk refractory patients simply these patients live much longer today with ibrutinib and simply they fortunately do have the time to then unfortunately experience Richter’s transformation which in the past simply wasn’t’ possible at all because they unfortunately so quickly died from their CLL. I think it’s clearly something that we are seeing, however, we are seeing it only due to the benefit that the drug is providing.

JG: Now, you’ve been involved in some of the studies looking at the mechanisms of resistance and, of course, there are other reasons why a patient may come off ibrutinib and then their disease progresses. We’ve seen data and we’re going to see more data at this meeting about how we manage such a patient. Should a patient be afraid of going on to ibrutinib because potentially of the speed with which the disease comes off if they’re not able to tolerate the drug or if they become resistant?

SS: Again we have to be careful about this data because this data then is looking specifically at this very, very small subset of patients who fail or come off ibrutinib for whatever reason. Historically the outcome has been very poor, how can it be otherwise? They failed all available therapy, then they went on ibrutinib and they had no other option. So it’s quite clear that they couldn’t gain therapeutic benefit because there was nothing available. I think with a bit longer follow-up the data look a bit different and now with other options becoming available with biologically targeted therapy such as PI3K inhibitors or agents targeting Bcl2 obviously these patients get more and more options. So clearly the few failures and possibly a not so good outcome of those should not distract from the overall great benefit that patients can derive from ibrutinib.

JG: So this isn’t so much a glass half full, glass half empty, this is a glass 90% full and people shouldn’t be…

SS: Yes, exactly. It’s almost two glasses that you have, a glass of white and a glass of red wine.

JG: Yes, OK. So in general terms is it your view that we will continue to see ibrutinib and other drugs in this class moving earlier and earlier in the treatment course of the disease?

SS: I think this is certainly the case. As I said already, the phase III trial will be presented here at ASH clearly providing evidence that there is benefit of this early treatment, obviously, and also in a very transparent way we have to talk about things like cost of these treatments and sustainability of these options. But our prime goal should obviously be and focus on delivering best possible care to our patients. From that perspective clearly these new agents provide dramatic advance.

JG: A lot of the studies have included a lot more elderly patients for whom chemoimmunotherapy is more difficult to deliver. Does that mean this is just a drug for the elderly?

SS: There’s this evolution, as you say. First it was used or investigated in trials among refractory patients, 17p minus population, and then among elderly where actually chemoimmunotherapy which provided great advance was not an option anyway at least, something like FCR intense treatments. Now we lack randomised comparisons so far in young and fit patients and the front line setting but when you look at the data that are presented at this meeting among elderly patients with ibrutinib single agent, well-tolerated treatment, the results look so good that in cross-trial comparisons with all caveats it’s tempting to speculate that in the future, provided that there is evidence provided, this may also be a very good treatment for young patients.

JG: So here we are, what we’re seeing again, a huge amount of data new in CLL at this meeting. Continued evidence to show that more targeted therapies completely revolutionise the way we think about CLL providing great options for our patients we never had before. Our challenge now to find out exactly how to use these drugs, but what we’re hearing clearly is patients should not be afraid of the complications of these agents. They should be more afraid of the disease and the good option they have from the treatment.