{"entity":{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","aka":["BTK C481S","C481S","BTK mutation","BTK resistance mutation","PLCG2 mutation","PLCG2","BCL2 G101V","G101V","BCL2 mutation","venetoclax resistance mutation","BTK inhibitor resistance","BTKi resistance","T474I","L528W","kinase-dead BTK mutation","non-covalent BTK inhibitor resistance"],"tldr":"When ibrutinib-type drugs stop working in CLL, the usual reason is a mutation at the exact spot the drug binds (BTK C481S) or just downstream (PLCG2); when venetoclax fails, a BCL2 G101V mutation loosens its grip. Each can be seen in blood months before the disease visibly relapses, and each points to a different next drug.","summary":"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.","asOf":"2026-09-17","links":[],"tags":[],"related":["btk","bcl2","gatekeeper-mutation","resistance","ngs","ibrutinib","acalabrutinib","zanubrutinib","pirtobrutinib","venetoclax","lisocabtagene-maraleucel"],"cancers":["cll","cll-relapsed","mantle-cell-lymphoma","waldenstrom"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Biomarkers"},"route":"/terms/btki-bcl2i-resistance-mutations/","neighbours":{"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"gatekeeper-mutation","kind":"term","name":"On-target resistance mutations (gatekeeper, solvent-front, compound)","route":"/terms/gatekeeper-mutation/"}],"drug":[{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"},{"id":"lisocabtagene-maraleucel","kind":"drug","name":"Lisocabtagene maraleucel","route":"/drugs/lisocabtagene-maraleucel/"},{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","route":"/drugs/pirtobrutinib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"},{"id":"zanubrutinib","kind":"drug","name":"Zanubrutinib","route":"/drugs/zanubrutinib/"}],"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","route":"/cancers/cll-relapsed/"},{"id":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","route":"/cancers/waldenstrom/"}]}}