Pharmacological profiling in CLL patients during pirtobrutinib therapy and disease progression.

Pirtobrutinib is a reversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy for patients with chronic lymphocytic leukemia (CLL) in BRUIN trial. These patients were previously treated with covalent BTK inhibitor (cBTKi) and either discontinued cBTKi or had disease progression during therapy. As a result, some patients had wild-type BTK while others had mutant BTK (mostly C481 site where cBTKi binds). All patients received pirtobrutinib monotherapy. Twenty-six patients with CLL from BRUIN were treated at MD Anderson and twenty-three were followed up for at least two years. We compared baseline features between patients who had progressive-disease versus those who remained on therapy during the first 24 cycles of pirtobrutinib therapy. We performed pharmacological profiling of peripheral blood mononuclear cells taken from patients at pretreatment, during pirtobrutinib therapy, and at progression. Relapsed/refractory CLL to prior cBTKi, baseline BTK mutations, unmutated IGHV, bulky lymph nodes, XPO1 mutation and complex karyotype were more prevalent attributes in the pirtobrutinib progressive-disease subgroup. Interestingly, among patients who had progressive-disease, only three patients had baseline wild-type BTK, while eleven had mutant BTK (mostly C481). As reported before, we also observed that C481S mutant clone was decreased during therapy while T474 mutant either developed or increased. We did pharmacological profiling in samples taken during pirtobrutinib therapy when disease is responsive and primary cells are sensitive to pirtobrutinib. We also analyzed sensitivity of CLL cells to other targeted and clinically available agents when patient had PD on pirtobrutinib and needed a new treatment regimen. Ex vivo pharmacologic profiling suggested that during pirtobrutinib therapy, peripheral blood mononuclear cells (CLL cells) became resensitized to ibrutinib and other targeted agents. Combination therapy, including ibrutinib and venetoclax, was effective regardless of genomic background and even after relapse from pirtobrutinib monotherapy.