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Bruton kinase inhibitors

Bruton tyrosine kinase (BTK) is a nonreceptor tyrosine kinase that plays a central role in the signal transduction of the B-cell antigen receptor and other cell surface receptors, both in normal and malignant B lymphocytes. 

B-cell antigen receptor signaling is activated in secondary lymphatic organs and drives the proliferation of malignant B cells, including chronic lymphocytic leukemia (CLL) cells.

 

BTK is widely expressed in many cells and has a critical role in  -cell maturation, antibody production and Fcy receptor mediated signaling pathways.

BTK inhibitors (BTKIs) are increasingly replacing chemotherapy-based regimen, especially in patients with CLL and mantle cell lymphoma (MCL). 

Bruton tyrosine kinase inhibitors are particularly active in patients with CLL and MCL, but also with Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft-versus-host disease. 

BTK Inhibitors bind  to the cysteine residue that position for 81 of BTK, and form of covalent bond with that amino acid.

BTK inhibition has the potential to reduce Fcy receptor mediated macrophage  function and reduce auto antibody production.

This bond inactivates BTK permanently, and new BTK must be regenerated for the B-cell receptor pathway to turn back on.

Current clinical practice is continuous long-term administration of BTKi, which can be complicated by adverse effects or the development of drug resistance. 

Bruton Tyrosine Kinase (BTK) inhibitors inhibit the enzyme BTK, which is a crucial part of the B-cell receptor signaling pathway. 

Certain B-cell leukemias and lymphomas use B-cell receptor signaling for growth and survival.

The rationale for using BTK inhibitors in cancer, therefore, is to block this signaling and trigger cell death.

Bruton Tyrosine Kinase (BTK) inhibitors are effective against:

Chronic lymphocytic leukemia (CLL)

Follicular lymphoma

Mantle cell lymphoma

Marginal zone lymphoma

Small lymphocytic lymphoma

Waldenstrom 

Other selective B cell malignancies

Chronic graft-versus-host disease.

Not all BTK inhibitors are approved for all these conditions.

The surface of each B-lymphocyte contains around 10,000 protein complexes called membrane-bound antibodies, called immunoglobulins.

All the membrane-bound antibodies for one particular B-cell are the same; however, between B-cells, the antibodies vary slightly in their variable portion, meaning that there is a lot of diversity among B-cell membrane-bound antibodies ranging to several billion.

When a foreign invader/antigen enters the body, such as a disease-causing bacteria or virus, there would likely be a B-cell with the right membrane-bound antibodies available to attach to it. 

Following a B-cell binding  to an antigen, it becomes activated with the help of certain T cells and starts cloning itself, making hundreds of thousands of copies, and these start to differentiate, taking on certain roles. 

Memory cells exist that can recognize the same antigen later, and effector cells that start producing unique antibodies for that particular invader.

B-cell receptors assist with binding, internalization, and processing of an antigen. 

Stimulation of B-cell receptors induces the activation of multiple enzymes, including Bruton tyrosine kinase (BTK) which is part of the B-cell receptor signaling pathway that communicates with other cells of the immune system and results in B-cell proliferation and activation.

B-cells account for up to 25% of all cells in some cancers. 

Infiltrating B-cells also play an important role in breast cancer and ovarian cancers.

By inhibiting the BTK enzyme involved in B-cell receptor signaling, BTK inhibitors cause detachment of malignant B-cells from cancer sites into blood, which results in cell death. 

BTK inhibition can reduce the proliferation rate of malignant B-cells and decreases the survival of malignant cells. 

The effects of BTK inhibitors also extends to nonmalignant cells, which accounts for their side effects.

Ibrutinib is associated with approximately 50% of patients developing minor bleeding), atrial fibrillation, 16% of patients, and hypertension in almost 40% of patients.

Patients who manifest progressive disease on ibrutinib, or who discontinue it abruptly, experience a more aggressive clinical progression of their disease and overlapping the discontinuation of ibrutinib with a subsequent line of therapy is recommended. 

Acalabrutinib has a more favorable safety profile than ibrutinib with high blood pressure occurring in 7% of patients, neutropenia in 11% and pneumonia in 10%. 

Severe bleeding is not common. 

Acalabrutinib may be preferred in patients unable to tolerate ibrutinib because of coexisting conditions or toxicities. 

 Zanubrutinib side effects include neutropenia (14%), anemia (8%), neutropenia (7%), and pneumonia (4%). 

High blood pressure was reported in only 3% of patients and atrial fibrillation in only 1.9%.

Minor hemorrhage was observed in 2.5% of patients.

Bleeding complications are common with BTKIs ranging from minor bruising to life-threatening bleeds including intracranial hemorrhage.

After three years of follow up more than half of patients on Ibrutinib have had a bleeding event.

The percentage of patients with severe hemorrhages from Ibrutinib ranges  from approximately 4-10%.

BTKis tend to block multiple pathways that augment platelet function, such as granule release, formation of pseudopods, and binding of collagen.

BTK second generation Inhibitors are more selective for BTK and this selectivity  primarily Impacts the agents side effect profiles rather than their advocacy.

Bleeding effects some more pronounced with Ibrutinib than with acalabrutinib.

People with a history of bleeding or an increased risk for bleeding with BTKIs.

Older patients and those on medication that effect bleeding such as antocoagulants, aspirin, certain nonsteroidal anti-inflammatory drugs, and selective serotonin reuptake inhibitors have increase risk of bleeding with BTKIs.

The most common mechanisms of resistance to BTK Inhibitors appears to be a mutation of BTK at the binding site of the drug.

This bond between the drug and BTK is changed from a very irreversible to reversible by a mutation.

 

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