Over the last decade, Bruton tyrosine kinase (BTK) inhibitors have transformed the treatment of chronic lymphocytic leukemia (CLL). Ibrutinib, the first approved covalent BTK inhibitor, improved patient outcomes compared with chemoimmunotherapy regimens, which were the previous standard of care. However, many patients must discontinue ibrutinib due to toxicity.

Second-generation covalent BTK inhibitors acalabrutinib and zanubrutinib were developed to address toxicity concerns. Although these therapies have an improved safety profile compared with ibrutinib, acquired resistance may limit treatment. Because all 3 covalent BTK inhibitors share common resistance mechanisms, switching from one to another upon disease progression is an ineffective strategy.

Noncovalent BTK inhibitors offer patients an opportunity to reestablish BTK inhibition following covalent BTK inhibitor therapy. Pirtobrutinib selectively and reversibly binds to the BTK protein, minimizing toxic off-target effects while bypassing key mutations that confer resistance to covalent BTK inhibitors. As such, pirtobrutinib demonstrates effectiveness in patients whose disease has progressed on a covalent BTK inhibitor. It is approved for use in adults with CLL or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a B-cell lymphoma 2 inhibitor. An investigational noncovalent BTK inhibitor, nemtabrutinib, also shows promising activity after prior exposure to covalent BTK inhibitor therapy.

How do you treat patients with CLL/SLL who progress on a covalent BTK inhibitor? Has the recent approval of pirtobrutinib in CLL/SLL altered your treatment decisions?