EHA 2015
Advances in the treatment and management of CLL
Prof Clemens Wendtner – Klinikum Schwabing, Munich, Germany
Prof Peter Hillmen – Leeds Teaching Hospitals NHS Trust, Leeds, UK
PH: Hello, I’m Peter Hillmen, Professor of Experimental Haematology, University of Leeds in the United Kingdom and we’re speaking from the 2015 European Haematology Association annual meeting in Vienna. I’m joined by my good friend Professor Clemens Wendtner from Munich, part of the German CLL Study Group, and we’re going to talk about the recent update of the new advances in CLL that we’re hearing at this meeting and in recent meetings. So, Clemens, what are some of the most impressive changes that we’ve seen at this meeting this week?
CW: This meeting in Vienna we see more and more data about the so-called novel drugs in CLL, so kinase inhibitors, BCL-2 inhibitors and they are taking over more and more. So there are data, especially in relapsed refractory patients where we can hardly offer chemo-immunotherapy any more but we should go for the new drugs like BTK inhibitors, PI3K inhibitors and BCL-2 inhibitors. So that’s really popping up here.
PH: So seeing the evolution of the trials, really, because we’ve heard about them over the last year or two, the randomised phase III with very early follow-up, we’re seeing some later follow-up. Are there any notable concerns that are being raised or suggestions of which are the best approaches to treat patients?
CW: With respect to the new drugs there is a good message that the data are quite stable. It seems that there is still a high risk group of patients with a defect on chromosome 17, so either deletion or mutation or even both, that do not do as well as the other ones, but still very good. A highlight at this meeting was that BCL-2 inhibition can induce complete responses in a high proportion of CLL patients with relapsed refractory disease, that’s really of utmost interest.
PH: So the B-cell receptor antagonist we’re already talking in clinical practice of ibrutinib either alone or idelalisib with rituximab. We’re seeing durable remissions now with acceptable tolerability but we’re starting to see the beginning of more novel combinations with these B-cell receptor antagonists with either other antibodies or chemotherapy. I know this meeting we’re seeing some of that data emerge.
CW: Yes, we have seen first data of combination of chemo-immunotherapy, in this case bendamustine rituximab plus ibrutinib, the so-called HELIOS trial. So it’s now the time that you can combine two… the first side different principles. So the chemotherapy and the new drugs and what we do see is that responses are even higher and the remissions are even deeper. Still data have to be followed up, so early data but very interesting. So HELIOS was one example.
PH: So just concentrating on the HELIOS study where we have BR which most people are now starting to accept as a standard for certainly relapsed non-17p deleted CLL and the control arm of BR in that trial was similar to what we would anticipate from the German CLL study group, from Kirsten Fischer’s paper three or four years ago. But the addition of ibrutinib to BR improves not only the responses, and in some cases MRD responses which were being seen, but also the duration of remission.
CW: Right. For the triple combination of bendamustine, rituximab plus ibrutinib the median PFS wasn’t even reached. So in contrast for the BR we have seen a 14 months median PFS, so something we have also described in our former phase II trial. So that’s impressive and we also do have more complete remissions in the triple combination arm including ibrutinib.
PH: One of the things that strikes me regarding the HELIOS data is that with the speed of movement with CLL trials and treatments the design of our trials, it’s hard to keep up. That trial was designed three years ago and we know a lot more in terms of survival and outcome for ibrutinib alone now. It wasn’t really designed to test whether there’s synergy between ibrutinib and bendamustine rituximab, there wasn’t in the ibrutinib only arm. The data for the ibrutinib BR arm isn’t that dissimilar to the RESONATE ibrutinib monotherapy arm so do you think we have the information yet that says that we know that ibrutinib and BR is better than BR but do you need the BR?
CW: I think there is still a big question mark. Also, as you lined it out, with the trial design it’s difficult but also let’s put it this way – I think we might also re-think a little bit the sequence of therapy is something we have to focus on so it’s not to be the most aggressive in the first round, so hit very hard in the beginning, we call it the ... principle. It’s true for acute leukaemias but maybe for chronic leukaemias like CLL it’s more wise to offer some kind of sequences also to the patients. When I get this with a new drug, a very deep remission is fine, but maybe combining a chemotherapy with one of the new drugs also has some side effects. We know that BR also has side effects, it’s not a non-toxic drug combination.
PH: And obviously chemotherapy-free treatments are attractive for patients and for us because of the potential toxicity, certainly of the more intensive treatments. We’ve seen data now with idelalisib with other antibodies as well as rituximab, so we’ve had the 119 trial which was idela-ofatumumab versus ofatumumab. What’s your impression of the results of that trial?
CW: I would say the data pretty much confirm what we have seen with rituximab. We have seen with the idelalisib plus ofatumumab a median PFS of roughly 17 months, that’s OK. We have reports of the combi of idela plus rituximab, this was 19 months. I wouldn’t count on these two months so very similar data. Also the toxicity profile seems to be similar; the immune phenomenon we do see with idela regardless of what kind of anti-CD20 you are using, so colitis might be an issue for a certain fraction of patients and pneumonitis, but very similar to the old data we have seen before with idela plus rituximab.
PH: So both the drugs are maturing nicely but we aren’t seeing really deep remissions, we’re not seeing the MRD negative remissions which, as you alluded to before, with venetoclax or ABT-199 we are seeing that. I think we’ll be seeing the update at this meeting from Andrew Roberts of the combination of venetoclax with rituximab and really quite impressive responses.
CW: As you lined out, we are talking now about complete remissions in more than 40% of patients with a chemo-free, not chemical free but chemo-free, combination with venetoclax plus an anti-CD20 so in this case rituximab. What is even more impressive in this trial Andrew Roberts showed is that a majority of at least half of the patients have an MRD negative status in the bone marrow. So it seems that there is a certain group of novel drugs that is also potent enough to clear the bone marrow.
PH: So we’re now moving towards combinations and moving, even with the novel agents, towards MRD eradication and potentially stopping therapy which I think is the first time we’ve seen it with the novel agents.
CW: Exactly. That’s an additional value, I would say, because some patients might be shocked when you tell them that they receive continuous treatment with these novel drugs. But maybe in the future we might offer also treatment with novel drugs for a limited period of time.
PH: So if you’re advising the general haematologist oncologist who is managing their patients with CLL, what’s your ideal treatment? How would you approach a front-line patient with CLL now?
CW: I think it’s still the time where we should offer chemo-immunotherapy for front line, adapted on fitness. So the FCR is not out, it’s a very good combination for fit, young patients. We think when they are getting older, so we can discuss whether this has to be 65 or something else, but when they are fit but still a bit older we would go more for benda rituximab but you see it’s chemo-immunotherapy in the front line. There is one exception, two exceptions – patients with a 17p deletion and TP53 mutation. When the country in Europe offers one of these new drugs like idela or ibrutinib they should be given to the patient.
PH: Because in reality patients who have had a short first remission or even a moderately long first remission will do worse with further chemo-immunotherapy and the maturation of the data with novel agents is certainly looking promising. What about transplant, because that’s always been an issue for those really high risk patients? Do you think we’ve moved on from there?
CW: There is at least some consensus by EBMT saying that for maybe frontline 17p you should first choose these novel agents if it’s successful in your country. The time comes for transplantation when the first failure on these new drugs happens, then you can bridge with a second novel drug but then it’s time to prepare for transplantation. I think the situation is a little bit more complex for refractory patients. I would only use the new drugs as a bridging for one year, maybe two years for a young, fit patient, but then would immediately send him to allogeneic transplantation. But we have to face the majority of patients is not 35 and super-fit, the majority of patients is old and not so fit. So the allogeneic transplantation is not the option for the majority of CLL patients.
PH: I think in my practice, certainly, where we’re offering even the younger patients allogeneic transplant at relapse or even 17p, they are voting not to have treatment, they prefer to stay on ibrutinib and idela rather than to take the risk of a transplant. Transplant has been pushed back a bit further. Whether that’s right or wrong is debatable.
CW: Still I think we have to carefully observe what happens with the secondary resistance to these drugs. So far 3% is quite low but we do not know what will be the truth in five or ten years.
PH: Thank you, Clemens. So, as you can see, the data that is now continuing to emerge at this EHA meeting and at recent meetings is really showing the promise and the realisation of the promise of these new drugs which has already changed the outlook for patients with CLL. We’re now seeing clear improvements in survival and more challenging times ahead with what we’re going to do in front-line and what we’re going to do with transplant. Clemens, thanks for joining me with this.
