{"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":[{"label":"Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib","url":"https://doi.org/10.1056/NEJMoa1400029"},{"label":"Mato et al., N Engl J Med 2023: pirtobrutinib after a covalent BTK inhibitor (BRUIN, 317 patients)","url":"https://doi.org/10.1056/NEJMoa2300696"},{"label":"Blombery et al., Blood Adv 2022: enrichment of BTK Leu528Trp on zanubrutinib and cross-resistance to pirtobrutinib","url":"https://doi.org/10.1182/bloodadvances.2022008325"},{"label":"Blombery et al., Cancer Discov 2019: the recurrent BCL2 Gly101Val mutation confers resistance to venetoclax","url":"https://doi.org/10.1158/2159-8290.CD-18-1119"}],"tags":[],"related":["btk","bcl2","gatekeeper-mutation","resistance","ngs","ibrutinib","acalabrutinib","zanubrutinib","pirtobrutinib","venetoclax","lisocabtagene-maraleucel"],"cancers":["cll","cll-relapsed","mantle-cell-lymphoma","waldenstrom","non-hodgkin-lymphoma"],"sections":[],"technologies":[],"targets":["btk","plcg2","bcl2"],"drugs":[],"companies":[],"institutions":[],"pathways":["resistance-routes-map","bcr-signalling","apoptosis-bcl2"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["The figures, from the papers that first reported each mutation. BTK C481S: whole-exome sequencing of paired baseline and relapse samples from six patients with acquired ibrutinib resistance found the cysteine-to-serine substitution in five of them and three distinct PLCG2 mutations in two, and neither was present in nine patients with prolonged lymphocytosis who were still responding (Woyach 2014). The non-covalent answer: pirtobrutinib gave an overall response of 73.3% in 247 patients who had already received a covalent BTK inhibitor, with median progression-free survival of 19.6 months (Mato 2023). Its own escape route is partly inhibitor-specific: the kinase-dead BTK L528W substitution was enriched in patients progressing on zanubrutinib, 7 of 13 against 1 of 24 on ibrutinib, and was enriched further under pirtobrutinib in two patients, who then responded to venetoclax (Blombery 2022). BCL2 G101V: found at progression in 7 of 15 paired patients and in none at study entry, first detectable 19 to 42 months into continuous venetoclax and anticipating clinical progression by many months, reducing BCL-2 affinity for venetoclax about 180-fold on surface plasmon resonance (Blombery 2019)."],"category":"Biomarkers","wikipediaChecked":"2026-09-22"},"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/"},{"id":"plcg2","kind":"target","name":"PLCG2","route":"/targets/plcg2/"}],"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":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-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/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}]}}