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http://dx.doi.org/10.3324/haematol.2022.281402DOI Listing

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Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders, and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib, and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib.

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  • Bruton tyrosine kinase inhibitors (BTKi) have significantly improved treatment for B-cell malignancies, but many patients stop using them due to side effects, with cardiac issues being the most common reason for discontinuation.* -
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  • Results indicated pirtobrutinib had a median time on treatment of 15.3 months, with notable side effects like fatigue and neutropenia; overall, it proved to be a safe and effective alternative for
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  • BTK is crucial in B cell signaling and is a target for treating B cell cancers and immune diseases; however, covalent inhibitors face challenges due to the C481S mutation in most patients.
  • The FDA's 2023 approval of Pirtobrutinib sparked interest in developing non-covalent, reversible BTK inhibitors, leading to the design of 11 candidates in this study.
  • Among these, WS-11 demonstrated the highest effectiveness with low IC values for both wild type and C481S mutation BTK, showing promising drug-like properties for future development.
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  • Richter transformation is a serious form of aggressive lymphoma found in about 10% of chronic lymphocytic leukemia patients, with no approved treatments and a grim outlook.
  • Pirtobrutinib, showing good results for patients with B-cell malignancies who have relapsed or are resistant to conventional therapies, is being studied for its safety and effectiveness in treating Richter transformation.
  • The study included 82 adult patients who received pirtobrutinib daily, tracking overall response rates and safety, with results indicating the drug was well tolerated and active in this difficult subset of cancer patients.
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  • Pirtobrutinib, a selective noncovalent Bruton tyrosine kinase inhibitor, was tested in a phase 1b trial for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) using combinations of pirtobrutinib and venetoclax, with some patients also receiving rituximab.
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