Journal
FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.687458
Keywords
Bruton's tyrosine kinase; chronic lymphocytic leukemia; B-cell receptor signaling pathway; ibrutinib; acalabrutinib; zanubrutinib
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Funding
- American Society of Hematology Scholar Award - NCI [R01 CA 213442]
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Targeting the B-cell receptor signaling pathway through BTK inhibition has shown significant efficacy in the treatment of CLL and B-cell lymphomas. Different selectivity of individual BTKis leads to differences in target-mediated and off-target adverse effects. Disease progression driven by histologic transformation or selective expansion of mutated CLL clones remains a major challenge, but new combination regimens and reversible BTKis hold promise for preventing and treating BTKi-resistant disease.
Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Covalent BTK inhibitors (BTKis) led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups with TP53 aberration and unmutated immunoglobulin heavy-chain variable-region gene (IGHV). Ibrutinib and acalabrutinib are approved by the US Food and Drug Administration for the treatment of CLL and other B-cell lymphomas, and zanubrutinib, for patients with mantle cell lymphoma. Distinct target selectivity of individual BTKis confer differences in target-mediated as well as off-target adverse effects. Disease progression on covalent BTKis, driven by histologic transformation or selective expansion of BTK and PLCG2 mutated CLL clones, remains a major challenge in the field. Fixed duration combination regimens and reversible BTKis with non-covalent binding chemistry hold promise for the prevention and treatment of BTKi-resistant disease.
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