BCL2 Inhibition in Leukemia - Episode 4

Current Therapeutic Paradigm for Relapsed-Refractory CLL

June 25, 2019

Harry Erba, MD, PhD:You alluded to a problem that we’re all going to have as we develop newer therapies that we’re using up front, and that is what to do with the patients who do relapse or have refractory disease. How are you starting to think about how to approach those patients, now that you have patients who may have been on immunochemotherapy long before these drugs or BTK inhibitors and venetoclax? What kinds of factors go into deciding how to treat them next?

Matthew Davids, MD, MMSc:I think 1 of the really interesting things that’s coming along is this idea that we’re going to get patients into a remission, for example, with venetoclax plus obinutuzumab as their frontline therapy. And then, let’s say 3 or 4 years later, the disease comes back. What do we treat them with then? I think my preferred choice would be venetoclax plus obinutuzumab again, because they responded once before. Hopefully they will respond again. We don’t know that yet. We need to show that, but we would be trying to use drugs of the mechanism that has been working for as long as we can before switching to a different mechanism and saving the next mechanism for when they become refractory to the initial mechanism. And we may find down the road that we could just treat patients with a year of venetoclax plus obinutuzumab once every 4 or 5 years and they never become resistant, and they do well for the rest of their lives. That’s 1 scenario, or we may find that the second time we treat them, they don’t respond, or they respond much less durably. Then we need to be more proactive about switching mechanism. That’s sort of how I think about that aspect of it.

You’re going to have patients who go through multiple lines of therapy, as you described, and I think that is where the CAR T [chimeric antigen receptor T-cell] data start to become very exciting. I personally had some patients who have been in that scenario in which they’ve been through chemoimmunotherapy, and BTK inhibitors, and venetoclax and responded to CAR T therapy and can have durable responses. It’s certainly very promising.

Harry Erba, MD, PhD:You’re not mentioning using immunochemotherapy in the relapsed-refractory setting. Is that dead?

Matthew Davids, MD, MMSc:I would say that’s pretty much dead.

Harry Erba, MD, PhD:Really? Wow.

Matthew Davids, MD, MMSc:Yes, yes.

Harry Erba, MD, PhD:Pretty confident there.

Matthew Davids, MD, MMSc:I think that the challenge with chemoimmunotherapy in the relapsed-refractory setting is that No. 1, the durability of the benefit is clearly going to be less than it was in the frontline setting. No. 2, you’re going to engender more clonal evolution, enriching for deletion 17p,TP53, and making these patients much more resistant even to the novel agent-based therapies you may want to use later. I do hear this commonly from some of my referring doctors: “This patient responded to BR [bendamustine-rituximab] for 5 or 6 years, so I’ll just give BR again. I might get only 3 or 4 years out of it, that would be good.” It would be good until they develop clonal evolution of the CLL [chronic lymphocytic leukemia]. Or even worse, they have to visit you for a myeloid disease.

Harry Erba, MD, PhD:Exactly.

Matthew Davids, MD, MMSc:There are a number of factors there, but I think now we have enough data suggesting that we should be using novel agents exclusively in the relapsed-refractory setting whenever we have access to those drugs.

Harry Erba, MD, PhD:Well, I definitely agree with your point about using a regimen that’s working, a mechanism of action that works if you get a good first duration of response. Definitely try it again. Don’t abandon things that are working.

Matthew Davids, MD, MMSc:Right.

Harry Erba, MD, PhD:It seems, though, that you’ve just drawn a distinction between immunochemotherapy because of clonal selection and other myeloid disorders and these new targeted therapies in that approach.

Matthew Davids, MD, MMSc:That’s a great point. I think that’s why we’re all so excited about the venetoclax-obinutuzumab regimen, because it’s the best of both worlds. It’s novel agent only, and it’s time limited. Before we had to choose. We could either do time limited with chemotherapy, which had all these different down-the-road consequences, or we could do novel agent but continuous therapy. But now we have the best of both worlds with this new regimen.

Harry Erba, MD, PhD:How about allotransplant?

Matthew Davids, MD, MMSc:There is still a role for allotransplant in CLL. It has certainly decreased over the years recently. But we still think about it for patients who have deletion 17p orTP53mutation, who get into remission. When they get into remission with, say, ibrutinib in the frontline setting, it’s something I always talk about with them if they’re young and otherwise fit, not necessarily that they need it as their next therapy. Burt, we know that venetoclax has only about a 67% response rate or so for those patients who progress on ibrutinib. And so I think it’s something we need to mention to our younger, fit patients. I’m hopeful that as CAR T develops, it will start to take over that place of allotransplant. But we still do have a 40% long-term progression-free survival rate with allotransplant in CLL. So it’s something we can’t ignore.

Harry Erba, MD, PhD:And CAR T-cell therapy is not yet approved in CLL, right?

Matthew Davids, MD, MMSc:No. Still investigational.

Harry Erba, MD, PhD:But clearly important. For BCL2 inhibition, do you check BCL2 levels or BH3 expression? Is there any biomarker? Or are the response rates so high that it doesn’t matter?

Matthew Davids, MD, MMSc:There’s no specific biomarker right now in CLL. The levels of protein of BCL2 are uniformly high in CLL patients, and we do a technique at Dana-Farber Cancer Institute called BH3 profiling, which actually looks at the functional levels of the different proteins and how they interact with one another. And that’s investigational. It’s something we’re looking into seeing if it could be a biomarker.

You have to look down the road at how well this predicts the durability of response, because most of the patients are going to respond initially. It’s been a little challenging to develop a biomarker in this space, and it’s not going to be a simple measure like BCL2 expression or something like that.

Harry Erba, MD, PhD:So we’ve talked a lot about how you choose the next line. Tell us a little bit about the data in your experience using venetoclax in that relapsed-refractory population.

Matthew Davids, MD, MMSc:The venetoclax experience started with monotherapy in the relapsed-refractory population, where the overall response rates were around 80% and complete remissions were in the range of about 20%. But certainly, the addition of rituximab seems to have benefited patients, and so the MURANO regimen had very deep and durable responses with only 2 years of therapy. And I think that’s really the advantage of that combination with rituximab. It allows you to get to time-limited therapy.

There are some nuances as to who can stop therapy or not. The way that the regimen was designed was that everyone will get 2 years of therapy and then stop, regardless of what stage their disease was in. We did find that patients who had MRD [minimal residual disease] that was detectable at the end of those 2 years tended to be the ones who were progressing. There’s some debate right now about whether certain patients may need more than 2 years of therapy, may need to switch to a different therapy if they’re not undetectable for MRD, or maybe even need an additional drug at that 2-year time frame. There are still a lot of interesting questions, I think, around the optimal way to treat relapsed-refractory CLL with venetoclax. We certainly learned a lot over the last few years in that respect.

Transcript edited for clarity.