A recent study evaluated 9 patients with R/R CLL who underwent pirtobrutinib therapy using single-cell DNA sequencing, and identified several BTK mutations (V416L, A428D, M437R, T474I, and L528W) that conferred resistance to both non-covalent BTK inhibitors and some cBTKis [65] (Fig. 2c). Here, BTK is linked to B-cell chronic lymphocytic leukemia.