Novel Combination Regimens for Chronic Lymphocytic Leukemia


Implications for treating chronic lymphocytic leukemia with small molecule combination regimens in the frontline setting.

Susan O’Brien, MD: Let’s talk a little about these exciting small molecule combinations. It seems like every large, randomized trial now being done anywhere is looking at this, but we have data from 3 trials. We have the ibrutinib, venetoclax combination from MD Anderson Cancer Center. I think that’s still the only one published. But we’ve seen multiple presentations on CAPTIVATE, which is the Pharmacyclics [LLC] trial. It has the same initial schema as the MD Anderson trial, namely a 3-month lead-in with ibrutinib, then a ramp-up of venetoclax, then 12 months of the combination. Then in the CAPTIVATE trial, of course, there were different cohorts depending on MRD [minimal residual disease] status at the end of that combination, or there was also a fixed-duration cohort, but the first 15 months were the same as the MD Anderson data. Now we have the GLOW trial, which is the first randomized trial, which compared ibrutinib and venetoclax to chlorambucil and obinutuzumab. Now we see some trials that are also throwing an antibody in there with the 2 small molecules. I know you’re familiar with these data. You can give us your thoughts on this.

Anthony Mato, MD, MSCE: I could give you my thoughts. I don’t know if I could make sense of it. It’s 2 different processes. The combination looks active. It can induce deep remission, it’s time-limited, either MRD-driven based on CAPTIVATE part 1, or fixed duration based on CAPTIVATE part 2 or the GLOW trial. What I’m still trying to get my arms around is how to determine the relative contribution of each of the components. Who should get a novel-novel combination instead of either the sequence of these drugs or venetoclax and obinutuzumab? From an MRD perspective, and even maybe a PFS [progression-free survival] perspective, they look kind of similar to me. It’s hard for me to judge the importance of the need for the combination based on the comparisons that are made. We’re joking around about chlorambucil and obinutuzumab. Everybody has been able to beat it; U2 [ublituximab, umbralisib] beat it, ibrutinib/obinutuzumab beat it, acalabrutinib/obinutuzumab, acalabrutinib monotherapy beat it, venetoclax/obinutuzumab beat it. Everybody seems to be able to beat it, but when you start putting drugs together, which individually were able to beat the control, it’s hard for me to really assess how this will impact my practice. I think it probably will be used in my practice, but probably for younger patients who have poor-risk features who want a time-limited approach. That’s kind of where I’m seeing this going at the moment.

Then you brought up the triplets. The triplets are interesting too, but I don’t have any triplet vs doublet vs mono data coming, none of us do, to decide who needs a triplet vs a doublet. So we’re starting to get into this quagmire where we have lots of active regimens, but comparisons that don’t really guide decision-making. That’s where I’m hopeful some of the newer trials, like the CLL17, at least are on the right track of asking how to judge contribution. That’s ibrutinib vs ibrutinib plus venetoclax vs venetoclax plus obinutuzumab, so really asking important questions like mono vs doublet, fixed duration vs continuous, novel-novel vs either of the individual components. That’s my take on the combinations at the moment.

Susan O’Brien, MD: I agree with you. Clearly, the patient population that stands to benefit the most are younger patients. The reason I say that is for older patients, if you think about it, the median age for diagnosis is about 71 according to SEER [Surveillance, Epidemiology, and End Results] data. Unlike this case that we presented, for the vast majority of patients you’re going to do watch and wait at the time of diagnosis. Let’s say you do a couple of years of watch and wait. Then we know from the long-term data from RESONATE-2 that at 7 years, there’s still no median PFS with the use of ibrutinib in the frontline setting, and at 6.5 years, 61% were progression free. Let me just go out in a limb and say maybe they’re going to reach a median at 8 years. You see where I’m going with this? My patient’s 71 [years old], I’ve done watch and wait, they’re 74 [years old]. They just got 8 years out of ibrutinib, so they’re 82. The MURANO trial of VEN-R [venetoclax, rituximab] was 1 prior regimen. It wasn’t ibrutinib, it was chemotherapy, but 1 prior regimen, and the median PFS was about 4.5 years.

It’s exactly what you said. If we sequence these treatments, except in very high-risk patients, and that even seems to be changing as we talked about in frontline 17p deletions. As we sequence these and consider the age of patients, do you really need the combinations? But of course, where you are really going to need them is with the hope that you can do better with the combinations and maybe even affect a cure. I don’t think anybody’s talking about that now, but certainly what we’d all like to do is get to a cure. I think MRD undetectability is essential for that, but it is not by itself enough. That may be partly because we standardly use 104 in our trials, and I think we need to be going forward, really looking at deeper levels which we can do now with these commercial assays to look at 105 or 106. We see that in a lot of these trials, they all come in at about 70% MRD undetectability at 104. What I would like to know is how do they compare at 105 or 106 because that might give us a better idea of long-term data. For younger patients, I think we still have the issue of probably not being able to cure those patients even with all the great drugs that we have without other things like CAR [chimeric antigen receptor] T-cell therapy or transplant, etc. Those are the people for whom I think the combinations are going to be really important.

Transcript edited for clarity.

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