BCL2 Inhibition in Leukemia - Episode 6

Is There Still a Role for Frontline Chemoimmunotherapy in CLL?

Harry Erba, MD, PhD:Before we get on to the future, I want to ask you something else. We now have venetoclax-obinutuzumab. We’ve had ibrutinib with rituximab, another combination we use up front. But I’m continuing to hear about patients actually starting with immunochemotherapy. Do you think there’s a reluctance to move to these? A lot of oncologists will say, “I want to save those. We know that they’re effective in the relapse setting. I don’t want to get to those now. I want to use chemotherapy.” Getting at what you said, what do you do when they progress after those drugs? What would you say to someone who still wants to use immunochemotherapy up front?

Matthew Davids, MD, MMSc:I think this is a very different discussion from the relapsed setting. That, to me, is very clear that we should not be using the chemoimmunotherapy in the relapsed setting. I think it’s much murkier in the frontline setting right now because there is still a role for chemoimmunotherapy. I think we need to be smart about where we use it and when we use it. The first thing is that if you’re considering using chemoimmunotherapy for frontline CLL [chronic lymphocytic leukemia], you have to test for FISH [fluorescence in situ hybridization] andTP53status, if you can, andIGHVstatus, because those are all the key variables that go into the equation on trying to decide if chemoimmunotherapy is the best regimen for my patient. So for patients withTP53dysfunction, chemoimmunotherapy clearly not the answer.

Now what about patients with unmutatedIGHV? There we have robust phase III frontline data now of ibrutinib against FCR [fludarabine-cyclophosphamide-rituximab]—actually ibrutinib-rituximab against FCR [fludarabine-cyclophosphamide-rituximab], but the rituximab probably doesn’t add too much, that’s the ECOG [Eastern Cooperative Oncology Group] study. Then we also have ibrutinib versus BR [bendamustine-rituximab] in the older patients. That’s the Alliance study. And in both those studies there are very dramatic PFS [progression-free survival] benefits for the unmutatedIGHVpatients who get the novel agent-based, ibrutinib-based regimen. I think that’s pretty compelling evidence.

You could make the case, even in the unmutated patients in the Alliance study, that there’s no overall survival benefit. That study did allow crossover. I think you can argue that 1 both ways for the older patients, where you might still be able to use BR [bendamustine-rituximab] and then use ibrutinib at relapse and the patients will live just as long. But I still worry about clonal evolution and myeloid neoplasia and some of these other longer-term effects. We don’t have long-term follow-up yet from that Alliance study.

In the frontline setting it’s a little bit different for the young patients because there was actually an overall survival benefit to the ibrutinib arm of that ECOG study over FCR [fludarabine-cyclophosphamide-rituximab]. And that benefit really was confined to those unmutatedIGHVpatients. For that group I was initially a little hesitant to use ibrutinib for the young patients, especially because of the idea of the continuous therapy. But it’s hard to argue with an overall survival benefit for that population. Even for my younger patients who have unmutatedIGHVnow, I think about using ibrutinib.

Harry Erba, MD, PhD:Yes, but let’s turn it to the mutated younger patient with a mutated CLL. There are The University of Texas MD Anderson Cancer Center data, German data, and I think Italian data all suggesting that in that population we may actually see a plateau on the overall survival, progression-free survival curves out 10, 15 years with immunochemotherapy.

Matthew Davids, MD, MMSc:That’s exactly right. And so that’s the 1 group right now that I still firmly believe that we should be offering chemoimmunotherapy: young, fit patients with mutatedIGHV. They can get 6 months of therapy and potentially functionally cured of their CLL. We do have to counsel them about some of the long-term risks of FCR [fludarabine-cyclophosphamide-rituximab] and long-term myelosuppression and myeloid malignancies, which are rare but can happen. I think now it’s interesting because we have venetoclax plus obinutuzumab that’s come along, and we have a different time limit of regimen that we don’t think has any of those longer-term risks, but we also don’t know what the long-term follow-up is going to look like and if there’s going to be a plateau or not. And so that’s where I’m saying it’s getting a little bit murkier in that respect.

Harry Erba, MD, PhD:Is it worth doing a study of venetoclax-obinutuzumab versus immunochemotherapy?

Matthew Davids, MD, MMSc:Yes. And there are studies like this that are in the works. It’s going to be, I think, challenging, though, to randomize patients in that way.

Harry Erba, MD, PhD:Yes.

Matthew Davids, MD, MMSc:Yes, it will be.

Transcript edited for clarity.