Bruton’s tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL)

ABSTRACT

Introduction: The BTK inhibitor ibrutinib is effective in both low- and high-risk CLL patients, achieving durable remissions with continuous therapy in the majority of patients. Ibrutinib lacks myelotoxicity and is generally well tolerated by older and unfit patients; however, side effects, such as atrial fibrillation or hemorrhage, can result in treatment interruption or discontinuation. Given the high efficacy and overall safety, ibrutinib is increasingly used in untreated and previously treated CLL patients. Second-generation BTK inhibitors are being developed, with different and generally more BTK-selective kinase inhibition profiles, which may increase the safety and/or efficacy.

Areas covered: We review key features of ibrutinib, along with problems of its use, discuss the potential and drawbacks of second generation molecules, and discuss combination therapies currently in development.

Expert Opinion: BTK inhibitors have been a major therapeutic advance in older/unfit patients and those with high-risk and/or relapsed CLL, but require indefinite maintenance therapy and risk of developing treatment resistance or adverse events requiring treatment cessation increases over time. Novel combination strategies are currently being evaluated (e.g. the combination of ibrutinib with venetoclax), which may achieve greater depth of remission, remove the need for indefinite maintenance treatment and potentially replace chemoimmunotherapy in the first-line setting.

KEYWORDS:

• BTK inhibitor
• ibrutinib
• acalabrutinib
• BGB-3111
• GS-4059
• SNS-062
• CLL
• chronic lymphocytic leukemia

Article highlights

• Development of Bruton Tyrosine Kinase (BTK) inhibitors, such as ibrutinib, has been a major advance in the treatment of CLL, particularly in the following settings: elderly and unfit patients, in the first line setting who could not tolerate chemoimmunotherapy; patients with high-risk features such as deletion 17p and/or TP53 mutations; patients with relapsed, particularly fludarabine-refractory CLL.

• BTK inhibitor therapy rarely achieves MRD-negative complete remission and therefore maintenance treatment is required. During maintenance treatment with ibrutinib, there is the risk of developing Richter Transformation, particularly in the first 18 months of therapy and subsequently, CLL progression, particularly in patients with del(17p) and/or complex metaphase karyotype. CLL progression occurs most commonly due to the development of point mutations in BTK, which prevent covalent binding of ibrutinib and/or activating mutations in phospholipase C-gamma 2 (PLCG2), which bypass BTK blockade.

• Unique side effects of ibrutinib, such as atrial fibrillation and bleeding due to platelet dysfunction create management challenges, in many cases leading to treatment discontinuation, which, if required increases relapse risk and decreases survival. Management of therapy-related toxicity to allow continued treatment is therefore important. Some of the side effects associated with ibrutinib may be due to off-target kinase inhibition.

• Second generation BTK inhibitors have been developed, with greater specificity for BTK, which may be associated with lower incidence of therapy-related adverse effects and are being evaluated in ongoing studies.

• Novels combinations of BTK inhibitors with CD20 monoclonal antibodies, BCL2 inhibitors and chemoimmunotherapy are being evaluated, which may achieve minimal residual disease-negative remissions and potentially obviate the need for indefinite maintenance treatment.

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Declaration of interest

P. A. Thompson has been a consultant and received honoraria from Pharmacyclics. J. A. Burger has received research support from Pharmacyclics and Gilead and has been a consultant for Janssen Pharmaceuticals. 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

J. A. Burger is supported by a Leukemia & Lymphoma Society Scholar Award in Clinical Research, the MD Anderson’s Moon Shot Program in CLL, and in part by the MD Anderson Cancer Center Support Grant CA016672.