William G. Wierda, MD, PhD: I mentioned that there were 2 large phase III randomized trials. The other one is what’s referred to as the MURANO study. That trial was designed based on a phase 1b trial that, Dr. Ma, you have presented at prior meetings with venetoclax plus rituximab. Now, venetoclax is approved in relapsed patients who have 17p deletion. There’s less restrictive labeling in Europe, but for the time being in the United States, we’re limited to prescribing it for patients who have relapsed disease with 17p. The trial that you were participating in enrolled relapsed patients. Maybe you can give us a little bit of perspective from that trial and then maybe summarize the MURANO results first.

Shuo Ma, MD, PhD: So, venetoclax is an orally available BCL-2 inhibitor, which is really targeting the apoptotic machine directly. The trial though, leading to the approval, was based on patients with 17p deletion. And then we have presented, in ASH 2015 and 2016, the combination of venetoclax with rituximab in previously treated patients. So, those patients who had a median prior treatment of 2. With that combination, we have seen a very high overall response rate of 86%, with a complete response rate of 51%.

And what’s more remarkable is the bone marrow MRD negativity. So, minimal residual disease negative bone marrow was achieved in 57% of the patients. These are relapsed/refractory patients, which is almost unprecedented, that we have seen with prior immunotherapy or other oral agents. So, that’s very encouraging, the depth and also the durability of the response. The progression-free survival has not been reached. The 2-year progression-free survival with the venetoclax and rituximab combination was 82%. So, very encouraging data from that phase Ib study.

And we also had a patient who actually, once they achieved MRD negativity, had the option to either stop or continue to the venetoclax monotherapy. So, there are 13 patients who actually stopped venetoclax treatment. Among the 13 patients, 2 of them were MRD-positive CR, and 11 of those were MRD-negative. So, the only patients who progressed to date are the 2 patients who had MRD positivity at the time when they stopped. That means that once you’re able to achieve the negative MRD status in the marrow, then those patients can potentially still have quite durable response of treatment.

William G. Wierda, MD, PhD: And do you expect reresponse when patients are retreated?

Shuo Ma, MD, PhD: Right. The 2 patients who relapsed once off venetoclax, actually, they relapsed about 24 months after stopping the treatment. And both of the patients were retreated with venetoclax rituximab and both of them had achieved response again.

Steven Coutre, MD: I actually have 1 patient like that from one of the early trials who was MRD negative and stopped for a year or 2, and then was able to go back on and respond to this.

Shuo Ma, MD, PhD: Right. Based on that very encouraging phase Ib data, the MURANO study was designed as a large phase III randomized study comparing venetoclax/rituximab versus the bendamustine/rituximab combination. So, you have a novel combination versus the conventional immunochemotherapy. These are for patients with relapsed/refractory CLL. And the MURANO study really showed that the response is fantastic and what’s more remarkable is that the progression-free survival was significantly prolonged in patients who were treated with the venetoclax/rituximab combination. Yes, the hazard ratio is 0.17.

William G. Wierda, MD, PhD: Nicole, can you comment on how you manage relapsed disease?

Nicole Lamanna, MD: Sure. I was going to bring up one point. What’s interesting about this, which we didn’t discuss, is that what’s different here is an antibody with venetoclax is clearly different than an antibody with ibrutinib. I think that we haven’t seen as impressive results when we add an antibody to ibrutinib. But I do think the combination with venetoclax is more striking. And so, whether it will be rituximab or obinutuzumab, I think that that combination is better than venetoclax alone.

William G. Wierda, MD, PhD: And just to elaborate, Jan Berger presented data from our trial. We had a randomized trial with ibrutinib plus or minus rituximab, and other than the cosmetic effect more rapidly bringing down lymphocyte count, the progression-free survival looks similar. There were a higher proportion of patients who were MRD-negative who got rituximab, but that hasn’t appeared to translate into anything meaningful in terms of the progression-free survival here. And I think that’s probably because everybody is remaining on ibrutinib. So, continuous therapy. MRD is less important and less of a relevant endpoint compared with time-limited therapy.

Nicole Lamanna, MD: I agree.

William G. Wierda, MD, PhD: So, maybe you can elaborate on your approach to relapsed disease, and what are the things that you’re thinking about when you’re selecting treatment for a relapsed patient.

Nicole Lamanna, MD: Absolutely. So, similar to what Matt had said earlier, part of it depends on what the patient might have received and how long their response was to that therapy. Of course, cytogenetics and their mutational status is relevant as well. We’ll just talk about a few examples of somebody. We have, obviously, some data where if you’re starting ibrutinib in the frontline setting, what happens then if you relapse? What do you go to then? We have little data when it comes to chemoimmunotherapy post TKI initiation.

Obviously, most of our patients had gotten chemoimmunotherapy and then received TKIs in relapse, so we know what that scenario is. And because there’s lots of those folks who were on those initial studies, if they then failed ibrutinib, their overall survival is poor. And so, that’s when folks were being transitioned to venetoclax, for example, and that certainly was able to salvage some of those patients; albeit those patients will drop off and will still need alternative therapies or clinical trials. Or, if they’re young enough to get a transplant or things of that nature.

So, I think in relapse if they’ve had chemoimmunotherapy and then have ibrutinib or a TKI, going to venetoclax is a reasonable approach. If they have a TKI as frontline and then they relapse, the question remains―although there are some presentations that we had at this ASH meeting looking at if you start them with an antibody and can you salvage ibrutinib―then can you salvage them or use chemoimmunotherapy? I think they are very young data but certainly, there’s a possibility that you could give chemoimmunotherapy in relapse, or a BCL-2 inhibitor, of course, after a TKI would certainly not be unreasonable.

So, that’s generally the approach that I’ve been taking if they’re not going on a clinical trial, if they’re multiply relapsed, and then get ibrutinib. I will transition them to venetoclax or venetoclax and an antibody. If they’re newly on ibrutinib and then they relapsed, a lot of them do not want to do chemoimmunotherapy. It’s just that we don’t have that data. But a lot of my patients won’t, so then they’re transitioning to venetoclax.

William G. Wierda, MD, PhD: Will the MURANO data drive whether or not you give venetoclax with rituximab?

Nicole Lamanna, MD: Yes. Certainly, in the era—although, again, with the TKI data, they have been less impressive—with venetoclax, I think it has been more impressive. In the chemoimmunotherapy data, whenever we added a monoclonal antibody, it did better. The venetoclax data, I think, suggest that as well. So I have no problem giving venetoclax and an antibody.

William G. Wierda, MD, PhD: We’re going to talk about the new agents in just a minute. But before we move on, maybe Steve, you can comment on acalabrutinib, which was recently approved for mantle cell. It’s a new BTK inhibitor and there was an abstract presented at this ASH which was an update with the acalabrutinib experience.

Steven Coutre, MD: Yes. So, it’s a first of the second-generation BTK inhibitors. It has a different profile than ibrutinib. It’s thought to be more specific of an inhibitor for BTK and so, theoretically, at least perhaps a different side effect profile. And what about AFib? What about the bleeding, the platelet dysfunction that you see? It is a b.i.d drug, that’s how it’s used as opposed to once a day. So, one has to consider patient compliance issues. And so far, the data are good. They certainly look as good from an efficacy standpoint in the relapsed/refractory patients. As you see with ibrutinib, there are updated data of that trial by Dr. Berger and colleagues at the ASH meeting. To be perfectly honest, it’s hard to truly draw conclusions about differentiation on side effect profiles. They are reporting less AFib. The bleeding, it’s hard to say. One peculiar side effect early on is headache, which I think is easily dealt with. But it’ll be interesting. They’ve done the appropriate trials. There’s an up-front trial compared to obinutuzumab/chlorambucil. There’s actually a head-to-head trial with ibrutinib in high-risk relapsed patients. There’s a trial for ibrutinib-intolerant patients. So, we’ll get good data. I think the drug will get approved for CLL and then we’ll see.

William G. Wierda, MD, PhD: So, for the irreversible BTK inhibitors, there’s an association with mutations in the cysteine 481 moiety, which is the target for the irreversible inhibitors. There are new ones that were presented or have been discussed at this meeting. Maybe you can briefly review what those are and what’s the direction…

Steven Coutre, MD: Sure. The one that comes to mind is the sinensis compound, and it’s interesting. It’s neat science to me, and it probably would work perfectly fine in those patients who have developed those specific resistant mutations. But I think, again, in the big picture, how common is that really going to be, especially as we move these drugs upfront? So, what role will it play except for an occasional patient? Time will tell.

Transcript Edited for Clarity