Chronic Lymphocytic Leukemia Resistance to Next-Generation BTK Inhibitors

Some patients treated with pirtobrutinib acquired mutations in Bruton tyrosine kinase binding domains that led to disease progression.

The covalent, irreversible-binding Bruton tyrosine kinase inhibitors (BTKis) ibrutinib, acalabrutinib, and zanubrutinib provide high response rates in both standard- and high-risk subtypes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). BTKi resistance may arise via an acquired mutation at C481 in the BTK binding site. Next-generation, noncovalent, reversible-binding BTKis, such as pirtobrutinib, are not blocked by this mutation.

Investigators now report novel, non-C481 BTKi mutations in patients treated with pirtobrutinib that confer resistance to it and other noncovalent BTKis. Peripheral blood and bone marrow samples were collected at baseline and during pirtobrutinib treatment in the phase 2/3 BRUIN clinical trial f…

Reviewing Author

Michael E. Williams, MD, ScM

Disclosures

Consultant/Advisory BoardAbbVie; AstraZeneca; Beigene; Janssen; Pharmacyclics

Grant/Research SupportJanssen

Editorial BoardsAmerican Board of Internal Medicine (ABIM) Hematology Longitudinal Knowledge Approval Committee

Michael E. Williams, MD, ScM

Disclosures

Consultant/Advisory BoardAbbVie; AstraZeneca; Beigene; Janssen; Pharmacyclics

Grant/Research SupportJanssen

Editorial BoardsAmerican Board of Internal Medicine (ABIM) Hematology Longitudinal Knowledge Approval Committee

Chronic Lymphocytic Leukemia Resistance to Next-Generation BTK Inhibitors

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Reviewing Author