Combination Therapies for Chronic Lymphocytic Leukemia


Susan M. O’Brien, MD, on combination therapies for treating patients with chronic lymphocytic leukemia.

Susan M. O’Brien, MD: We’re seeing more and more combinations now, either of small molecules with antibodies, predominantly obinutuzumab [Gazyva] at this point, or combinations of small molecules with or without an antibody. We know that there were 2 clinical trials that showed that adding 6 months of rituximab [Rituxan] to ibrutinib [Imbruvica] did not affect the long-term progression-free survival. It was the same as if ibrutinib was given by itself. It is interesting that in the ELEVATE TN trial [NCT02475681], which was the trial of acalabrutinib [Calquence] and obinutuzumab, there was an arm with acalabrutinib alone. Now with the 4-year data, we’re seeing that those remissions with the combination appear to be longer. It’s obviously a different BTK inhibitor and it’s a different antibody. My suspicion is that the difference in the BTK inhibitor might not be as important as the fact that obinutuzumab is a much more potent antibody than rituximab. It was only given for 6 months just like in the rituximab trials where the BTK inhibitors continued indefinitely, but the monoclonal antibody is stopped after 6 cycles. That data appears to be very different than the previous data, and my guess is that it’s because of the antibody. Up until now, nobody was giving antibody with rituximab or acalabrutinib for the most part because the data were all negative. This is the first positive data that we’ve actually seen at the spring meetings this year.

Right now, most people use BTK inhibitors as a single agent. By contrast, most people use venetoclax [Venclexta] in combination because although venetoclax’s original approval was as a single agent and given continuously so you can use it that way. People are very attracted to the finite therapy trials. We have the venetoclax and obinutuzumab frontline approval, with the duration of venetoclax being 1 year, and then the relapse trial was venetoclax and rituximab. The antibody was front loaded for 6 cycles, but the venetoclax was continued for 2 years. Most people, when they’re using venetoclax, are using the combination regimens more frequently. As I mentioned, we’re starting to see small molecule combinations and there will be a lot of presentations involving these combinations at [the American Society of Hematology Annual Meeting] this year. This really appears to be the wave of the future. Some of them are with just small molecules without antibody, and some are with antibody. Some of them are randomized trials where there’s also a chemotherapy arm. Lots of that data will be at ASH this year and it’s very exciting data.

We know from some of the nonrandomized trials, for example, the MD Anderson data [NCT02756897] that were the first published combining ibrutinib and venetoclax or the CAPTIVATE data [NCT02910583] which was the Pharmacyclics trial combining ibrutinib and venetoclax, that were getting very high rates of MRD [minimal residual disease] undetectability, which implies that their emissions will be very durable. That’s what allows you to potentially have finite therapy, which everybody’s very interested in. The combinations are clearly where we’re going, and we don’t know which is the best combination. We don’t know if adding an antibody will be important. All of those are very active questions that are being explored in clinical trials.

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