Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

ABSTRACT

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 ≈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.

KEYWORDS:

• BTK inhibitors
• chronic lymphocytic leukemia
• ibrutinib
• PLCG2

Declaration of interest

JR Brown has served as a consultant for Pharmacyclics, Janssen, Astra-Zeneca, Acerta, Sun, Abbvie, Gilead, Infinity, Verastem, Roche/Genentech and TG Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

BL Lampson is supported by the NIH Training Grant 2 T32 CA 9172-42 A1. Jennifer Brown is supported by National Institutes of Health (NCI 1R01CA213442-01A1, NIH 1U10CA180861-03, and P01CA206978-01), and the Susan and Gary Rosenbach Fund for Lymphoma Research, the Melton Family Fund for CLL Research and the Okonow/Lipton Family Lymphoma Research Fund.