Rationale for BTK Inhibition in CLL

Ian Flinn, MD:Hello, and thank you for joining thisTargetedOncology™ presentation titled, “The Evolving Role of BTK Inhibitors in Treating Chronic Lymphocytic Leukemia.”

Treatment for chronic lymphocytic leukemia has evolved in recent years from standard chemoimmunotherapy approaches to strategies based on novel targeted agents. Today we are going to talk about the evolution of Bruton tyrosine kinase [BTK] inhibitors, which are now central to the treatment of CLL [chronic lymphocytic leukemia].

I am Dr Ian Flinn, the director of the lymphoma research program at the Sarah Cannon Research Institute in Nashville, Tennessee.

Joining me today is Dr Jan Burger, a professor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, Texas.

Thanks so much for joining us. Let’s begin.

Jan, let’s start with some basic biology and rationale for BTK inhibitors in treating B-cell lymphomas. Can you walk us through some of the logic there?

Jan A. Burger, MD, PhD:Thanks, Ian, for the introduction. I think 1 of the fundamental questions is what is BTK, and why is it emerging as such a successful therapeutic target for CLL patients? BTK, or Bruton tyrosine kinase, is a kinase in the cells of CLL cells that is very essential for transmitting signals from the surface of CLL cells into the cell. And its main role is related to the B-cell receptor, which is a key molecule on B lymphocytes and also on CLL cells. I think that’s been 1 of the major discoveries of the last 1 or 2 decades, that the B-cell receptor is so important for CLL biology.

When that gets activated, it transmits signals that the CLL cells need for growth and survival. The signal goes into the cells with the help of these enzymes called kinases, and BTK is 1 of the key kinases. If you don’t have a functional BTK kinase, which actually can happen in patients who have a very rare immunodeficiency called XLA [x-linked agammaglobulinemia], those patients have mutations in BTK and they can’t make any functional B lymphocytes. So it is very important for the growth, for the survival of normal B cells.

What is interesting for the CLL side of things is that if you block it in patients with CLL, then you induce patients to go into remission. So it has emerged during the last decade, I would say, as the most successful therapeutic target. It is expressed in normal and in malignant B cells. And if you make a hierarchy in terms of efficacy for various diseases, then I think No. 1 would be chronic lymphocytic leukemia where we get very durable remissions and the vast majority of patients—almost all—respond. But it’s also active in other B-cell malignancies, and maybe you want to comment on which other diseases it’s effective in and where is it approved? Do you have an idea why is it so successful in CLL and why is it maybe not as active in other diseases like DLBCL [diffuse large B-cell lymphoma]?

Ian Flinn, MD:You brought up a number of interesting things you talked about. First of all, you talked about anemia, XLA, taking a disease and learning from the biology of that and turning it on its head and making the therapy for these B-cell malignancies, which I think was really fascinating and really tremendous early work in this field. But prior to BTK inhibition, certainly in many diseases, for instance, chronic lymphocytic leukemia, we were talking about chemoimmunotherapy and all the off-target toxicities that you would get, the collateral damage from the chemotherapy that surrounds it. And that’s true beyond just CLL. That’s true in mantle cell lymphoma and other diseases.

We have multiple ones that are now approved by the FDA for the treatment of mantle cell lymphoma, but we also have 2 that are approved for chronic lymphocytic leukemia: acalabrutinib and ibrutinib. Really, these drugs have changed the treatment paradigms completely for many different B-cell malignancies, including diseases like Waldenström macroglobulinemia. Those paradigms have changed dramatically.

Transcript edited for clarity.