BTK C481S, PLCG2 and BCL2 G101V resistance mutations

What is measured: acquired mutations in BTK, PLCG2 and BCL2 that explain progression on targeted therapy. How: sensitive next-generation sequencing or digital PCR on peripheral blood CLL cells (or cell-free DNA) at progression or on surveillance. BTK C481S accounts for over 80 percent of resistance to the covalent inhibitors (ibrutinib, acalabrutinib, zanubrutinib), with C481R/F/Y variants; T474I and L528W arise on pirtobrutinib and zanubrutinib and, being kinase-dead, also resist pirtobrutinib; PLCG2 gain-of-function mutations (R665W, L845F, S707Y) act downstream; BCL2 G101V (and D103Y and others) appears in about half of venetoclax relapses, often subclonal and up to two years before clinical progression, but not typically in patients treated for a fixed duration and retreated after a gap. What a result changes: covalent BTK inhibitor failure with C481S leads to pirtobrutinib (BRUIN) or a venetoclax-based regimen; kinase-dead mutations lead to venetoclax, BTK degraders in trials, CAR-T (lisocabtagene maraleucel is approved for CLL) or bispecific antibodies; a BCL2 mutation leads to a BTK inhibitor or trials and makes venetoclax retreatment less reliable; a rapidly growing node is biopsied for Richter transformation before any switch. Where it matters: CLL, relapsed CLL, mantle cell lymphoma and Waldenström's.