CLL: Combination Strategies and Unmet Needs

Susan M. O’Brien, MD: We’re now beginning to get into the point where we’re combining small molecules either with antibodies or with other small molecules. Right now, I’m unconvinced there’s a role for antibodies with B-cell receptor inhibitors. The data are clear with any of the antibodies that have been used so far that when you add the antibody, you get a much faster response, because you abrogate the lymphocytosis that we see with the B-cell receptor inhibitors. But there are no clear data that we get more durable remissions or deeper remissions with antibodies.

In contrast to that, I think the data with venetoclax in combination with antibodies are much more compelling, and that’s true whether we look at rituximab or obinutuzumab, where we see the MRD-negativity rates really go up dramatically when the antibody is added in. So, I think that in contrast to ibrutinib or the B-cell receptor inhibitors, there is synergy when we add an antibody to venetoclax.

One of the unmet needs historically in CLL was the treatment of patients with 17p deletion, because we know that these people have poor response rates to chemoimmunotherapy, and that’s true irrespective of what that immunotherapy was. And even if they did get a response, they had very short remission duration. That unmet need to some extent has been dramatically met by the small molecules, because we now have ibrutinib and we also have venetoclax, and both of them are very potent and active agents in patients with 17p deletion.

So, we still have the unmet medical need, I would say, of curing the majority of patients. We can potentially cure the mutated patients who are fit with FCR, but what about the rest of the patients? And I think that that’s still an unmet need. We do want to keep people alive as long as possible, but ideally, we would like to cure them, and so I think that’s something we’re still striving to accomplish in most of the patients with CLL.

I think the future of the treatment with CLL is going to be combinations of small molecules either with or without antibodies. And I think that there are some very interesting data combining ibrutinib and venetoclax—again, with or without antibodies, depending on which trial you’re looking at. And these are very exciting, because what they’re showing is very high rates of MRD negativity. And we like that not just because it’s a really deep response but also because it raises the possibility of finite therapy and being able to stop rather than going continuously with the small molecules, like we do now.