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Targeting BTK in B-Cell Malignancies

Insights From: Brad S. Kahl, MD, Washington University School of Medicine; Steven P. Treon, MD, PhD, Harvard Medical School
Published: Wednesday, Mar 13, 2019



Transcript: 

Brad S. Kahl, MD: BTK is an enzyme called Bruton tyrosine kinase, and it’s an enzyme that appears to be important in normal B-cell development. There are actually inherited conditions in which people have mutations in that gene, and they don’t express normal amounts of BTK. And these individuals grow up with an immunodeficiency that makes them prone to significant infections. It wasn’t obvious that targeting BTK would be a good therapeutic strategy in B-cell malignancies, but it turns out that it is a good therapeutic strategy in some B-cell malignancies. Targeting BTK turns out to be very effective in chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, and even marginal zone lymphoma. All of these diseases can be quite sensitive to targeting BTK with novel agents that attack the BTK protein.

BTK is important in normal B-cell development. People who are lacking that enzyme have trouble making normal healthy B cells and have an immunodeficiency state. And BTK appears to be important in B-cell receptor signaling. So a normal, healthy B cell has a job to do in your immune system, and it will receive signals. The B-cell receptor will recognize antigens, different infections, and things that the B cell comes across. And so BTK helps transmit signals from outside the cell to the nucleus of the cell, so it’s part of a signaling pathway. It just so happens that some B-cell malignancies are quite dependent on the signaling pathway for their survival. If you can disrupt the signaling pathway with BTK inhibition, you can cause these cells to die.

BTK inhibitors have been under study in B-cell malignancies for about 10 years now. It became obvious, very quickly, that they were quite active in a subset of patients, and the first BTK inhibitor was approved back in 2013. So they’ve been on the market now for over 5 years, and we’re getting more and more experience treating people with BTK inhibition and are actually getting some long-term data now on efficacy and safety. Each year we learn a little bit more about BTK inhibition and how good it is and what the kind of pearls and pitfalls of treating people with BTK inhibition are.

Steven P. Treon, MD, PhD: Bruton tyrosine kinase, or BTK, is a very important kinase. It actually triggers NF–kappa B [nuclear factor–kB] growth and survival in these cells. What we discovered in our laboratory was that the mutated MYD88 was able to activate BTK. This was a very important revelation because it gave us a very targeted therapy in a disease in which 95% to 97% of all patients actually carry an activating MYD88 mutation. And it’s through BTK that it’s able to transactivate NF–kappa B growth and survival. So being able to target BTK is very important in Waldenström.

When you inhibit Bruton tyrosine kinase, you’re actually shutting down NF–kappa B growth and survival. And in most B-cell malignancies, including Waldenström, NF–kappa B is a very important growth and survival pathway.

Transcript Edited for Clarity
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Transcript: 

Brad S. Kahl, MD: BTK is an enzyme called Bruton tyrosine kinase, and it’s an enzyme that appears to be important in normal B-cell development. There are actually inherited conditions in which people have mutations in that gene, and they don’t express normal amounts of BTK. And these individuals grow up with an immunodeficiency that makes them prone to significant infections. It wasn’t obvious that targeting BTK would be a good therapeutic strategy in B-cell malignancies, but it turns out that it is a good therapeutic strategy in some B-cell malignancies. Targeting BTK turns out to be very effective in chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, and even marginal zone lymphoma. All of these diseases can be quite sensitive to targeting BTK with novel agents that attack the BTK protein.

BTK is important in normal B-cell development. People who are lacking that enzyme have trouble making normal healthy B cells and have an immunodeficiency state. And BTK appears to be important in B-cell receptor signaling. So a normal, healthy B cell has a job to do in your immune system, and it will receive signals. The B-cell receptor will recognize antigens, different infections, and things that the B cell comes across. And so BTK helps transmit signals from outside the cell to the nucleus of the cell, so it’s part of a signaling pathway. It just so happens that some B-cell malignancies are quite dependent on the signaling pathway for their survival. If you can disrupt the signaling pathway with BTK inhibition, you can cause these cells to die.

BTK inhibitors have been under study in B-cell malignancies for about 10 years now. It became obvious, very quickly, that they were quite active in a subset of patients, and the first BTK inhibitor was approved back in 2013. So they’ve been on the market now for over 5 years, and we’re getting more and more experience treating people with BTK inhibition and are actually getting some long-term data now on efficacy and safety. Each year we learn a little bit more about BTK inhibition and how good it is and what the kind of pearls and pitfalls of treating people with BTK inhibition are.

Steven P. Treon, MD, PhD: Bruton tyrosine kinase, or BTK, is a very important kinase. It actually triggers NF–kappa B [nuclear factor–kB] growth and survival in these cells. What we discovered in our laboratory was that the mutated MYD88 was able to activate BTK. This was a very important revelation because it gave us a very targeted therapy in a disease in which 95% to 97% of all patients actually carry an activating MYD88 mutation. And it’s through BTK that it’s able to transactivate NF–kappa B growth and survival. So being able to target BTK is very important in Waldenström.

When you inhibit Bruton tyrosine kinase, you’re actually shutting down NF–kappa B growth and survival. And in most B-cell malignancies, including Waldenström, NF–kappa B is a very important growth and survival pathway.

Transcript Edited for Clarity
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