Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and alternative treatment strategies

ABSTRACT

Introduction

Development of the BTK inhibitor ibrutinib has changed the landscape of CLL treatment producing durable responses with minimal to no myelosuppression. Although remissions are durable, relapses remain a challenge.

Areas covered

Data from recent studies indicate that most patients relapsing on ibrutinib have mutations in BTK or PLCG2. The result of the C418S mutation in BTK is loss of covalent binding of ibrutinib to BTK resulting in reversible, transient inhibition in BTK mutant patients. There is downstream gain of function of BCR signaling with PLCG2 mutations allowing continued cell proliferation despite inhibition of BTK by ibrutinib. Agents targeting other pathways such as the BCL2 pathway, or agents binding to other BTK binding sites are promising therapies in patients with BTK-mutated resistance. Authors conducted a review of available literature on mechanism of ibrutinib resistance and management using PubMed, Medline, EMBASE, Cochrane Central, Google Scholar, and ClinicalTrials.gov.

Expert opinion

The current approach is to offer a clinical trial or the BCL2 inhibitor venetoclax to patients with ibrutinib-resistant CLL. We await more data from ongoing clinical trials combining different targeted therapies or using reversible BTK inhibitors will provide more options for overcoming ibrutinib resistance.

KEYWORDS:

• Leukemia
• ibrutinib
• chronic
• resistance
• mutation
• BCR
• BTK
• lymphocytic
• inhibitor
• CLL

Article highlights

• Most of the CLL progressed on ibrutinib have mutations in BTK (C481S) receptor or in PLCG2 which is downstream in BCR signaling.

• Upfront combinations of different targeted therapies with a fixed duration of treatment could possibly prevent resistance resulting from the emergence of a resistant clone driven by continuous treatment of ibrutinib.

• In the setting of ibrutinib failure, venetoclax therapy appears superior to both idelalisib and chemoimmunotherapy.

• Preclinical data as well as data from early phase clinical trials has demonstrated that the reversible BTK inhibitors are effective against both wild type and C481S-mutated BTK.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.