Journal
EXPERT REVIEW OF HEMATOLOGY
Volume 11, Issue 3, Pages 185-194Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/17474086.2018.1435268
Keywords
BTK inhibitors; chronic lymphocytic leukemia; ibrutinib; PLCG2
Categories
Funding
- NCI NIH HHS [P01 CA206978, UG1 CA233338, T32 CA009172, R01 CA213442, U10 CA180861] Funding Source: Medline
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Introduction: Ibrutinib is the first BTK inhibitor to show efficacy in chronic lymphocytic leukemia (CLL) and is also the first BTK inhibitor to which patients have developed resistance. Mutations in BTK and PLCG2 are found in approximate to 80% of CLL patients with acquired resistance to ibrutinib, but it remains unclear if these mutations are merely associated with disease relapse or directly cause it.Areas covered: Unique properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease are reviewed. Characteristics of mutations that drive drug resistance are summarized and whether BTK/PLCG2 mutations possess these is discussed. These characteristics include (1) identification in multiple patients with acquired resistance, (2) in vitro validation of drug-resistant properties, (3) mutual exclusivity with one another, (4) increasing frequency over time on drug, and (5) high frequency at the time and site of clinical relapse.Expert commentary: While BTK/PLCG2 mutations have characteristics suggesting that they can drive ibrutinib resistance, this conclusion remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant CLL. Data suggest that alternative mechanisms of resistance do exist in some patients.
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