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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.
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.
In plain words · The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.
Showing the target this term concerns: BTK (Bruton tyrosine kinase).
Shares PLCG2, Pirtobrutinib, Zanubrutinib, B-cell receptor / BTK signalling (to NF-κB).
Shares Intrinsic apoptosis (BCL-2 family), Resistance routes: how a blocked pathway comes back, BCL-2, Next-generation sequencing (NGS).
Shares Pirtobrutinib, Zanubrutinib, Acalabrutinib, Ibrutinib.
Shares Pirtobrutinib, Zanubrutinib, Acalabrutinib, Ibrutinib.
Shares Zanubrutinib, Acalabrutinib, BTK (Bruton tyrosine kinase), Ibrutinib.
Shares Zanubrutinib, B-cell receptor / BTK signalling (to NF-κB), Acalabrutinib, BTK (Bruton tyrosine kinase).
Shares Acalabrutinib, Relapsed or refractory chronic lymphocytic leukaemia, BTK (Bruton tyrosine kinase), Ibrutinib.
Shares Acalabrutinib, Relapsed or refractory chronic lymphocytic leukaemia, Ibrutinib, Chronic lymphocytic leukaemia.