ASCO 2015

ASCO 2015: Latest in chronic lymphocytic leukaemia

Prof Stephan Stilgenbauer - Universitätsklinikum Ulm, Ulm, Germany
Dr Jacqueline Barrientos - LIJ Medical Center, New York, USA

SS: Hello, and welcome everybody to a new edition of ecancer.tv. My name is Professor Stephan Stelgenbauer from Ulm University and I’m here today with Jackie Barrientos, Professor Jackie Barrientos, from North Shore University. Jackie, welcome very much; thank you for joining us. It has been exciting times here at ASCO again this year regarding CLL developments overall, I think. Can you tell us a bit what excited you most about the new developments in CLL biology and therapy that we have in front of us?

JB: So it’s an amazing time for our patients. They are all now able to get access to these drugs that in clinical trials we knew had unprecedented results, not only in terms of response rates but also in terms of remission durations. Now we are seeing more mature data. It is an amazing time to know that our patients now have options of care. If for any reason they are unable to tolerate one drug they might be able to get access to a different drug that is not chemotherapy per se, so it has a much more safety profile than traditional chemotherapy options and they feel also very energetic and they feel great when they go into remission. So it’s an amazing time for our patients because I can only think that the future is just starting. In the process these new agents have opened up a new pipeline of new drugs and we’re all excited about that in the field.

SS: Absolutely, I couldn’t agree more. I think it’s particularly exciting that this precision medicine or translational approach in science, in clinical medicine, really here materialised. We understand the disease biology, we have BTK, PI3K, BCL-2, we have been knowing that they are relevant for disease biology for quite a while but now we can really tackle them with these new agents. So what do you think? There have been some trial data here presented on new safety issues on combination also with chemotherapy, for instance ibrutinib with BR, what do you think of these data? How do these translate to our practice, maybe tomorrow?

JB: So now we have more solid and mature data of what we kind of knew in combination of these targeted agents with chemotherapy or chemo-immunotherapy approaches. Ibrutinib with bendamustine and rituximab has shown improved overall response rates, improved rates of complete remissions and longer progression free survivals to the point that the trial was stopped early to allow the patients to cross over to ibrutinib. But it’s still coming to us the question of what do we do in the future? Do we still give our patients BR in combination with ibrutinib or should we just give ibrutinib? That is a question that is currently being answered in the United States. We have a clinical trial where we randomise the patients to receive either BR or ibrutinib as a single agent or ibrutinib in combination with rituximab and hopefully in the next couple of years we’ll figure out which one is the best combination for our patients. There was no evidence of any increased toxicities when ibrutinib was combined with chemotherapy so that might be other options of care for the future, for front line therapy for young patients that might be able to receive chemotherapy with ibrutinib.

SS: So this is the chemotherapy free future that we’ve all been dreaming about?

JB: Yes.

SS: Apparently in trials already it’s materialising, also in the front line setting. On the other hand we have to say there are some new safety issues, there are some rare side effects of these novel agents, even if they’re only low grade they are sometimes worrisome. Can you tell us a bit about new understanding, new data from this ASCO meeting that we have on these issues?

JB: Yes, absolutely. A couple of the trials, what we have noted, for example with the BTK inhibitor ibrutinib, which is the first in class BTK inhibitor available in the United States and in Europe, is that patients may find more bruises on their skin but they may also have more bleeding events. Additionally, there are some issues with arrhythmia that have been reported and arthralgia, which means joint pain. So this is not typical of what we see with chemotherapy and that is something that people have to understand, that it’s a known side effect of the drug and that they need to report it to their private doctors or their oncologist. In the sense of the PI3K delta inhibitor idelalisib, which is the first in class PI3K delta available in the United States and in Europe, what we see is mainly three events that have a black box warning in the United States. One is that your liver function enzymes may go up or increase to levels that are dangerous so your doctor has to monitor your liver function enzymes every two weeks at least.

SS: So transaminitis.

JB: Transaminitis, yes. They have to stop it and do a drug holiday and then re-challenge at a lower dose. The other one is colitis, which is a very severe secretory diarrhoea, non-bloody, non-infectious, that resolves with the initiation of steroids like budesonide or oral steroids and stopping the drug. Patients can tolerate the drug when they are re-challenged later on. And last but not least, pneumonitis, which is a severe inflammation of the lungs that can cause severe shortness of breath or low oxygen levels. So any cough that doesn’t go away, any shortness of breath, you need to report it to your doctor. So these are things that we traditionally don’t see with chemotherapy so it’s very important to be aware of these side effect profiles so that we can give these drugs safely to our patients.

SS: We’ve been discussing now these new side effects, these AEs as we call them in trials. Overall I think we still have to say that these new agents are very safe and certainly also from an efficacy perspective much better than anything that we had available before for these patients. So clearly we have to be careful of monitoring the patients and not prescribing a pill and sending them home but look at these patients still very carefully.

JB: Yes, and the dangers occur immediately. Immediately there’s a decrease in the size of the lymph nodes. What may accompany the use of these drugs is the white blood cell count may go up and that may make some people scared, but it’s a transient process, eventually the lymphocytosis, the white blood cell count numbers go down and it remains low. So it’s interesting that these drugs work in a different pathway affecting the signalling mechanism that makes the white blood cell count go up but it doesn’t mean that you are progressing. So it’s a different safety profile but, again, excellent results and excellent outcomes, so we’re very excited. Living in exciting times.

SS: So can you maybe, just to be clear, sum up for general practice what the licensed indications at the moment are for the new agents and maybe also what you expect in the near future with regard to broader license of these agents?

JB: Right now, for example, in the United States ibrutinib is approved for any patient that has a 17p deletion. We know that 17p deletion patients behave very badly, they don’t traditionally respond to chemotherapy and, in my opinion, giving them chemotherapy is giving them less than the standard of care. The standard of care should be targeted agent.

SS: Very important. So we should test for these abnormalities.

JB: Absolutely, test before starting any therapy and wait for the analysis of cytogenetics and FISH analysis to detect the 17p deletion.

SS: OK, very important.

JB: The other important thing to know is that in Europe, European markets, idelalisib is approved in combination with rituximab for 17p deletion patients but not in the US. But it is my understanding that with all the data that is emerging of how the drug has activity in 17p, hopefully the FDA will look into this data and accept that the drug has activity and accept it also as an alternative in case you are not able to tolerate ibrutinib. So these two drugs have good activity in 17p deletion patients. We also are seeing ABT-199, which is venetoclax, the FDA recently gave it breakthrough designation for 17p deletion patients so we are hopeful that in the future this drug will also be an option of care for our patients with 17p deletion.

SS: And then outside the 17p population, which you made clear is a totally different thing, it’s almost CLL, it’s 17p minus CLL in a way, it’s a particular disease, isn’t it in a way? So outside the 17p minus setting, both of the agents are licensed for relapsed refractory CLL in general aren’t they?

JB: For relapsed refractory because that’s where the clinical trials were done. But currently we’re doing clinical trials in the front line setting, that means for patients that have never been exposed to any prior therapy. We’re hopeful that the trials will pretty soon come out with the data that shows that they’re safe and efficacious as well. The big question, or the big elephant in the room, will be is chemotherapy better for a young and healthy patient or will it be a targeted agent or a combination of targeted agents. Currently we have two large clinical trials in the United States on-going and it’s very important for people to know about these trials because then they can get access to these new agents. For young, healthy patients there’s a randomised trial giving FCR or ibrutinib in combination with rituximab. And FCR, as of today, is the standard of care for young, healthy, fit patients. The other trial is for elderly unfit patients, they are randomised to either bendamustine and rituximab against ibrutinib or against ibrutinib in combination with rituximab. Both trials will essentially figure out which combination is best for front line therapy and will follow them up also for progression free survival. They also want to determine whether the side effect profile is similar or one of those arms is better. We still don’t know if, for example, there’s a subgroup of patients that are treated with FCR that essentially ten years later are still in remission, about a third of the patients. So would these type of patients benefit from taking a drug continuously for several years or should we just decide that this is the patient population that we should treat with chemotherapy in front. It’s a question that we need to answer.

SS: And these trials are underway, as you say.

JB: Yes.

SS: So you outlined very elegantly to us the use of these agents as they are licensed now, about ibrutinib and idelalisib. You also indicated that ABT-199 or venetoclax is already on the horizon. Given these success stories, what is your take on what is coming down the road? What are the new agents that are in early development or entering clinical trials now?

JB: Now we know that, for example, the PD1 inhibitors, or checkpoint immune inhibitors, are now available in solid tumours. I think that that’s the next step, to move into the haematological field and maybe combinations of PD1 inhibitors with these new agents or other combinations of B-cell signalling agents or anti-CD20 monoclonal antibodies in combination. I believe that the German CLL study group is going to do a venetoclax with ibrutinib with obinutuzumab trail, so I think the data and safety from these clinical trials will be of immense importance to us. Because we might be entering that era of not using chemotherapy until you have been failing everything else.

SS: But still, as you alluded to, it is important to stress that with FCR and maybe also bendamustine, rituximab, so chemo-immunotherapy in general, also including ofatumumab and obinutuzumab with chlorambucil, we have really years and decades of experience and we have these patient populations, as you say, that stay in remission, sometimes even MRD negative, for five, six, seven, eight or more years. So clearly we have not to discard chemotherapy at this moment; we need these trials, as you say, to develop the field further but still in the front line setting would you agree that chemo-immunotherapy is certainly a valid treatment option for the majority of patients?

JB: Absolutely, yes. And that’s the reason why we’re doing the clinical trials – we still don’t have an answer for that.

SS: OK, so a reason to do more trials to develop more agents and to test them against and maybe combined with chemo-immunotherapy. What do you think?

JB: Yes, that’s probably… it’s in our DNA to combine things, I believe, it’s part of being an oncology doctor. We always like the success of one drug and then think how can we make it better.

SS: Right, I mean beginning with childhood ALL and Hodgkin’s disease, combining agents has been the way to cure. It is somehow hard to believe for us that single agent treatment could do the same, although for ibrutinib and rituximab and idelalisib we have agents that clearly outperformed combination chemotherapy, at least in some settings already, didn’t we?

JB: Yes, we did.

SS: OK, so it’s exciting times, you would agree?

JB: Amazing times, yes.

SS: And we are looking forward to the next meetings, maybe ASH later this year, to see the next updates of these trials. Good. Thank you very much again, Jackie.

JB: Thank you very much.

SS: That was a great session and we hope to meet you again in the future and discuss the new trial results. Thank you very much.

JB: Great, thank you.