The Future of Targeted Management for CLL

Transcript:Anthony Mato, MD, MSCE: BCL2 inhibitors are here to stay in hematologic malignancies. They are active in CLL [chronic lymphocytic leukemia] in the relapsed-refractory setting as a continuous therapy, specifically talking about venetoclax in combination with rituximab in the relapsed-refractory setting, and in combination with obinutuzumab. This is established. The BCL2 inhibitors, specifically venetoclax, are being combined with ibrutinib and other novel agents in CLL. These same combinations are also being explored across B-cell malignancies. And while there are differences for sure, in terms of biology and rates of response and depth of response, I do think that BCL2 inhibitors will play a role in managing other B-cell malignancies. These include both indolent disease and also more aggressive diseases, like diffused large-B-cell lymphoma or the most aggressive variants of that—the double-head lymphomas or the semitranslocated lymphomas.

I think the data right now for BCL2 inhibitors, either alone or in combination in lymphoma, are less well established. But I expect diseases like mantle cell and large cell to have opportunity to have this class of drugs be part of a standard of care in the future.

BCL2 inhibitors, because they’re active as single agents, are now being combined with everything. The most promising combinations appear to be those with either anti-CD20 antibodies or in combination with other targeted agents, specifically either PI3K inhibitors—there’s a trial that’s just opening looking at the combination of umbralisib, ublituximab, and venetoclax—or with BTK inhibitors. For example, a trial was recently published in the New England Journal of Medicine looking at the combination of ibrutinib plus venetoclax, and triple combinations looking at ibrutinib plus venetoclax and obinutuzumab were recently published in Blood and will be presented at the ASH [American Society of Hematology Annual] Meeting & Exposition next year.

I think the challenge from all these combinations is trying to decide who needs a BCL2 inhibitor by itself or with an anti-CD20, or with a targeted agent, or with a targeted agent and an anti-CD20 antibody. There are some randomized trials that are sort of touching at these questions, but there’s no definitive data yet to help us understand who requires what level of intensity of targeted agent-based therapy.

Because we have an expanded understanding of biology in CLL, the number of potential targets that are available for treatment options continues to expand. You know, it was only a relatively short time ago when the B-cell receptor and its signaling pathway were elucidated enough to the point that we could imagine developing drugs to target individual steps within that pathway. Not long ago at all.

The first targeted agent, ibrutinib, and then idelalisib were approved only in 2014. As we understand that pathway, there are additional potential targets that are being developed in various stages of development looking at either upstream or downstream targets. I don’t want to call them next generation, but there are alternative BTK inhibitors that are just being developed that may have different AE [adverse effect] profiles but similar activity.

We learn about resistance to these drugs, and then there are BTK inhibitors that are in development, which may bind differently to BTK such that they could overcome specific mutations at the Cys481 site.

There are other targeted agents focusing on the cell surface. There are antibodies to ROR1 that are in development. There are antibodies to CD19, obviously CD22 that are in development, possibly CD38, which is being studied. There are other internal targets like BCL2; as I mentioned, some previous studies are looking at venetoclax. But also other proteins within that family, which can be targeted particularly in the setting of resistance. MCL1 is 1 that comes to mind. And so the more we learn from the basic scientists and the translational biologists about B-cell receptor signaling, B-cell biology, and how malignant cells in CLL differ from normal lymphocytes, the more we’ll be able to exploit those differences and develop single-agent targeted therapies and then combinations of those therapies that are more rationally designed than just putting drugs together.

Transcript Edited for Clarity