Abstract
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.
Highlights
Bcell receptor (BCR) signaling is an essential component of normal B cell development and malignant B cell survival (Figure 1)
We focus our discussion here on the successes and challenges of Bruton’s tyrosine kinase (BTK) inhibition in chronic lymphocytic leukemia (CLL), a malignant B cell disease with the most abundant data available on this topic
The combination of an anti-CD20 monoclonal antibodies (mAbs) and a BTK inhibitors (BTKis) is generally well tolerated, and its use is supported by U.S prescriber information for ibrutinib and acalabrutinib
Summary
Bcell receptor (BCR) signaling is an essential component of normal B cell development and malignant B cell survival (Figure 1). Patients with unmutated IGHV, another high-risk genetic marker in CLL, achieved superior PFS with BTKi-based therapy compared to chemoimmunotherapy [37,38,39, 49]. Such PFS benefit was not observed in the subgroup with mutated IGHV. The combination of an anti-CD20 mAb and a BTKi is generally well tolerated, and its use is supported by U.S prescriber information for ibrutinib and acalabrutinib It is unclear if mAbs add clinically meaningful benefit to BTK inhibition. The ELEVATE-TN study reported 50% reduction in risk of progression or death in patients treated with acalabrutinib plus obinutuzumab compared to those receiving
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