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BTK Inhibitors in Chronic Lymphocytic Leukemia

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Medically reviewed by Dr. Brian Koffman

What is Bruton tyrosine kinase (BTK)?

BTK is a type of enzyme known as a kinase that adds phosphate groups to other molecules, such as proteins. This phosphorylation is part of a signaling cascade that causes other molecules in the cell to become active or inactive. BTK is part of the B-cell receptor (BCR) pathway, critical for B-cell function and survival. In CLL, BCR activity is upregulated, meaning the cancer turns up the activity, leading to increased proliferation and less natural cell death. CLL cells become “addicted” to BCR stimulation, and blocking it by blocking BTK has a profound beneficial effect in controlling CLL.

Why is BTK important in chronic lymphocytic leukemia (CLL)?

BTK is a good therapeutic target in CLL because it is only critical for the function of B-cells, and thus loss of BTK is not lethal for the patient. Moreover, it plays an outsized role in CLL cells compared to normal B-cells. BTK inhibition in CLL cells does not result in massive immediate killing of CLL cells like venetoclax or chemotherapy. Still, it does deprive the CLL cell of key signals for proliferation and survival, leading to eventual cell death. The first approved BTK inhibitor, ibrutinib, revolutionized the treatment of CLL and SLL and significantly improved patient outcomes.

How effective are BTK inhibitors?

BTK inhibitors are given as daily oral drugs, which must be taken continuously. BTK inhibitors produce rapid clinical responses and improvements in quality of life, but they are not curative. As a first-line therapy, treatment with a BTK inhibitor results in remissions of at least four years (and much longer for some) in 80% of patients. In relapsed or refractory CLL, treatment with a BTK inhibitor results in a median progression-free survival of 3 to 4 years.

How do BTK inhibitors work?

The three approved covalent BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) bind irreversibly to cysteine 481 (C481) on BTK, which completely inhibits the enzyme’s activity and blocks B-cell receptor signaling. There is also a new class of BTK inhibitors in development, called noncovalent BTK inhibitors, which bind reversibly (non-covalently) to a different area of BTK, so they do not require C481 for binding.

How does resistance occur?

Over time, CLL cells can develop mutations at the C481 site on BTK, which prevent covalent BTK inhibitors from binding. Because all the covalent BTK inhibitors use the exact binding mechanism, none of them will work if one drug stops working. Approximately 13 to 37% of patients discontinue covalent BTK inhibitors due to loss of efficacy and development of resistance. Several other mutations can also lead to resistance.

What’s different about noncovalent BTK inhibitors?

Noncovalent BTK inhibitors bind reversibly to a different area of BTK, so they do not require C481 for binding. Pirtobrutinib is a non-covalent BTK inhibitor approved for mantle cell lymphoma and is still being tested in clinical trials for CLL. Its use on CLL is now part of the well-respected NCCN guidelines, so it can be used “off-label” in CLL. It has been shown to have activity in most patients with C481 resistance mutations, so it could potentially extend the benefits of BTK inhibition for patients who had to discontinue covalent BTK inhibitor therapy. However, it is possible to develop resistance mutations to non-covalent BTK inhibitors through different mutations. Other noncovalent BTK inhibitors (e.g., nemtabrutinib and fenebrutinib) are under development, and we are still learning about their safety and efficacy.

How might combinations be used?

BTK inhibitors are also being tested in various time-limited double and even triple combination treatments to see if they can produce deeper remissions and better patient outcomes. If patients reach uMRD, they may be able to stop treatment and enjoy a long period of being in remission, off medications.

What are BTK degraders?

A new class of drugs in development is also known as BTK degraders. These drugs break down the whole BTK protein to completely eliminate it. While BTK inhibitors are like switches that turn off BTK, BTK degraders remove the protein entirely. Because BTK degraders erase the whole protein, they are effective even if there are resistance mutations to BTK inhibitors in the protein. Experimental BTK degraders are currently in early-stage clinical trials (see our previous coverage from ASH 2022 on NX-2127 and on BTK inhibitor resistance mutations) to learn more about these open clinical trials. It’s very early, but the data are promising.

Links and Resources:

The source article can be found here, but it is paywalled: Inhibiting BTK in Chronic Lymphocytic Leukemia

Take care of yourself first.

Ann Liu, PhD