The Role of BTK Inhibition in the Treatment of Chronic Lymphocytic Leukemia: A Clinical View

Abstract

The B cell receptor (BCR) signaling pathway is functional and has critical cell survival implications in B cell malignancies, such as chronic lymphocytic leukemia (CLL). Orally administered small molecule tyrosine kinase inhibitors of members of the BCR signaling pathway have proven to be transformational in treatment of CLL. The first-generation inhibitor, ibrutinib, covalently binds to the C481 amino acid of Bruton's tyrosine kinase (BTK), thereby irreversibly inhibiting its kinase activity, and interferes with the biology of the cells, ultimately resulting in CLL cell death and therapeutic response. Remissions are not deep to the point of considering discontinuation for most patients, but BTK-inhibitor-based therapy provides exceptional long-term disease control with continuous treatment. There are in-class toxicities and more selective second- and subsequent-generation agents and reversible inhibitors have been developed with the intent of reducing toxicities. Also, strategies to subvert resistance have included tighter or alternative, non-covalent, inhibitor binding. Furthermore, other strategies to deplete BTK protein, such as degraders, are in development and being tested in the clinic. Ultimately, the development and approval of these agents targeting BTK have ushered in a new era of chemotherapy-free treatments with remarkably improved survival outcomes for patients with CLL.

Keywords: BTK; Bruton’s tyrosine kinase; CLL; acalabrutinib; chronic lymphocytic leukemia; ibrutinib; pirtobrutinib; targeted therapy.

Figure 1

B Cell Receptor Signaling Pathway and Inhibition of BTK. Surface membrane of a B cell demonstrating surface B cell receptor and down-stream signaling molecules that participate in providing pro-survival, proliferation, migration, and apoptosis signals to the B cell, including CLL cells. Inhibitors of BTK that block this signaling are shown below, including inducers of degradation, irreversible and reversible inhibitors of BTK kinase activity.