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    Association details:
    Biomarker:BTK C481S
    Cancer:Chronic Lymphocytic Leukemia
    Drug:Imbruvica (ibrutinib) (BTK inhibitor)
    Direction:Resistant
    Evidence:
    Evidence Level:
    Resistant: C3 – Early Trials
    New
    Source:
    Br J Haematol
    Title:

    Screening and monitoring of the BTK C481S mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy

    Published date:
    05/21/2021
    Excerpt:
    ...83 relapsed/refractory CLL patients during single-agent ibrutinib treatment. With a median follow-up time of 40 months, BTK C481S was detected in 48·2% (40/83) of the patients, with 80·0% (32/40) of them showing disease progression...
    DOI:
    10.1111/bjh.17502
    Evidence Level:
    Resistant: C3 – Early Trials
    Source:
    EHA 2020
    Title:

    BTK AND PLCG2 MUTATIONS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA RELAPSING ON IBRUTINIB: A EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC) STUDY BASED ON REAL-WORLD EVIDENCE

    Published date:
    06/12/2020
    Excerpt:
    Thirty-one of 59 (53%) R/R pts carried at least 1 hotspot BTK mutation (p.C481S/R/Y) (median VAF 23.3%, range, 1.4%>97.3%) (Table 1). Eight of 31 (26%) mutated pts carried ≥2 hotspot BTK mutations with different VAFs. Seven R/R pts harboring BTK mutation(s) also carried PLCG2 mutation(s) (Table 1)....This study reveals that ~50% of pts relapsing on ibrutinib had a BTK p.C481 mutation by NGS.
    Evidence Level:
    Resistant: C3 – Early Trials
    Source:
    NEJM
    Title:

    Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib

    Excerpt:
    Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib….Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs.
    DOI:
    10.1056/NEJMoa1400029
    Evidence Level:
    Resistant: C3 – Early Trials
    Source:
    Nat Commun
    Title:

    Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

    Excerpt:
    ...we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A)...
    DOI:
    https://dx.doi.org/10.1038%2Fncomms11589