Chronic Lymphocytic Leukemia Resistance to Next-Generation BTK Inhibitors

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 for relapsed/refractory CLL (NEJM JW Oncol Hematol Jul 2021 and Lancet 2021; 397:892). All patients had prior therapy that included covalent BTKis.

Twelve of 55 patients (22%) developed disease progression on pirtobrutinib therapy; 9 had available baseline and postprogression clinical samples. Multiple non-C481 BTK mutations were identified that mediated resistance to pirtobrutinib as well as other noncovalent BTKis and certain covalent BTKis. Resistance was also mediated in some cases by downstream transcriptional activation of PLCγ2 or AKT that, in turn, supported B-cell receptor signaling and tumor cell survival, despite ongoing BTKi therapy.