With a better understanding of its biological characteristics, there has been a shift in therapeutic options from chemoimmunotherapy to targeted therapy. However, the latter are not yet curative. They are expensive, have a specific toxic effect, and ultimately lead to the development of resistant clones of tumor cells. Therefore, clinicians are faced with a growing number of patients with resistant disease. This is especially true in the development of resistance to Bruton’s tyrosine kinase (BTK) inhibitors, usually through the acquisition of a somatic variant that alters the protein binding site.
Despite their malignant nature, CLL cells remain sensitive to external signals in the lymph nodes: in this sense, they resemble healthy, mature B cells. Numerous signals from the microenvironment collectively drive the increased expression of “survival-promoting proteins” and the activation and proliferation of malignant B cells. Thus, the surroundings of lymphoid tissues, such as the lymph nodes and spleen, provide a protective niche for CLL cells, and their recycling between blood and lymphoid tissue is a fundamental component of the state’s homeostasis.
BTK is a non-receptor tyrosine kinase that is a component of the signal transduction pathway that mediates the response of B cells to search for their antigen. Its activation is necessary for the localization and retention of healthy B cells, as well as LLC cells in lymphoid tissues. In fact, upon binding of the B cell receptor (BCR) to the surface of CLL cells, a signaling cascade is initiated that leads to changes in the expression of genes that control proliferation and survival (Figure 1). BTK is a downstream component of the BCR pathway and plays an important role in maintaining LLC. Because BTK is only critical to B cells and loss of function is not lethal to the host, it represents an attractive therapeutic target since its inhibition should be specific to B cell inhibition. Deletion of BTK in an LLC cell does not result in immediate cell death, but deprives the LLC cell of proliferation and survival signals.
Figure 1: Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia.
The introduction of covalently linked BTK inhibitors (ibrutinib, acalabrutinib, tirabrutinib, and zanubrutinib) has significantly improved the treatment and prognosis of advanced CLL. When taken daily by mouth, a BTK inhibitor produces a rapid clinical response and improved quality of life, although a cure remains elusive. The response to BTX inhibitors is initially accompanied by an increase in the number of lymphocytes, which reflects the loss of localization of LLC cells in the lymph nodes and, possibly, in other lymphoid tissues. In patients with relapsing disease who received significant prior treatment, BTK inhibitors are associated with a median progression-free survival of 3–4 years. As first-line therapy, treatment with a BTK inhibitor results in remission lasting more than 4 years in about 80% of patients.
However, a significant number of patients receiving these drugs discontinue therapy due to side effects, which are mainly caused by inhibition of kinases other than BTK. The most common side effects leading to discontinuation of treatment are cardiac arrhythmias, especially atrial fibrillation, and pneumonia. In addition, 13 to 37% of patients discontinue these BTK inhibitors due to loss of efficacy and development of resistance. Discontinuation of a BTX inhibitor due to toxic effects is more common in those receiving ibrutinib, while discontinuation of a BTX inhibitor due to development of resistance occurs with any of the BTX inhibitors.
All approved BTK inhibitors bind covalently to a cysteine residue (Cys481) within the ADP-binding pocket of the BTK protein resulting in complete inhibition of its activity. The binding is irreversible and can only be “overcome” by the formation of new BTK proteins by the cell. An inevitable consequence of continued inhibition is the development of somatic variants of BTX, which reduce the activity of these inhibitors. The most common variants directly affect the Cys481 residue, resulting in reversible and unstable binding between BTK and its inhibitors. Less common are acquired “gain-of-function” variants in the gene encoding the downstream kinase PLCγ2 (PLCG2). This results in long-term BCR signaling occurring alone or in combination with BTK variants.
Non-covalent binding inhibitors do not require Cys481 for binding. Rather, they bind via hydrogen, ionic bonding, and hydrophobic interactions in a reversible manner to the ADP-binding pocket. Although pirtobrutinib is active in patients with Cys481 variants, other variants have been shown to be associated with loss of binding of both classes of inhibitors (covalent and non-covalent), so it is possible that the efficacy of non-covalent inhibitors is also limited by some of the somatic variants that occur in BTK.
Other non-covalent BTK inhibitors (eg, nemtabrutinib, fenebrutinib, and vecabrutinib) are in development, but how well they will treat tumors with resistant mutations (other than Cys481) has yet to be determined. Clinical trials are evaluating a new class of drugs that degrade the BTK protein. These BTK degraders induce proteasomal degradation of BTK proteins and appear to work well against CLL regardless of variant status.
Another approach is time-limited combination therapy. The idea is to avoid the resistance that occurs in response to prolonged exposure to the drug. The results confirm the safety of pirtobrutinib, making it a candidate for new combination therapies for the treatment of chronic lymphocytic leukemia. BTK inhibitors such as pirtobrutinib can also be combined with bispecific T cell antibodies to overcome the acquired T cell dysfunction that occurs in CLL and makes T cell targeted therapy difficult.
BTX inhibition in chronic lymphocytic leukemia
Arnon P. Cather, MD, PhD, and Barbara Eichhorst, MD
Department of Hematology, Cancer Center Amsterdam, Medical Centers of the University of Amsterdam, University of Amsterdam, Amsterdam (APK); and Department I of Internal Medicine and Center for Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, University of Cologne, Cologne, Germany (BE).
N Engl J Med 2023; 389:83-86