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Jennifer R. Brown, MD, PhD


Genomic Analysis Focuses on Mechanisms of Resistance to Noncovalent BTK Inhibitors in CLL

By: Sarah Campen, PharmD
Posted: Thursday, March 17, 2022

Resistance to noncovalent Bruton’s tyrosine kinase (BTK) inhibitors in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) may develop through on-target BTK mutations and downstream phospholipase C gamma 2 (PLCγ2) mutations that allowed escape from BTK inhibition, according to results from a genomic analysis published in The New England Journal of Medicine. Some of these mutations conferred resistance across covalent BTK inhibitors as well.

“These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors,” stated Omar Abdel-Wahab, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues.

Of 55 patients with relapsed or refractory CLL who were enrolled in the phase I/II BRUIN study, the researchers identified 9 patients with acquired mechanisms of genetic resistance to the noncovalent BTK inhibitor pirtobrutinib. A total of seven patients developed acquired mutations in BTK outside the C481 residue, and two patients had persistent PLCγ2 mutations that were identified prior to treatment; no new C481 mutations were identified. Additionally, no other recurrent mutation or copy number alterations were identified in those with disease progression.

The mutations that were clustered in the kinase domain of BTK—V416L, A428D, M437R, T474I, and L528W—conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Transcriptional activation reflecting B-cell receptor signaling persisted despite continued treatment with pirtobrutinib.

“More analyses of larger samples are necessary to characterize the frequency of these genetic events and how they will influence treatment options,” concluded the study authors.

Disclosure: For a full list of the study authors’ disclosures, visit

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