Changes in BTK clonal architecture under treatment with cBTKi followed by ncBTKi. CLL cells predominantly become resistant to cBTKi by acquiring mutations in C481 of BTK (yellow) that abrogate drug binding. ncBTKi can eliminate the C481 mutant clones. However, in patient subsets, minor subclones in the T474 gatekeeper residue or mutations affecting BTK function (red or blue) can occur under cBTKi. These non-C481 mutations can be clonally selected or newly acquired during ncBTKi treatment, leading to PD. WT, wild-type. Figure created with biorender.com. Jebaraj B. (2025) https://biorender.com/wj8ct2m.