Ibrutinib for the treatment of chronic lymphocytic leukemia

ABSTRACT

Introduction: Chemoimmunotherapy has improved outcomes in chronic lymphocytic leukemia, yet it is not curative, with very high relapse rates, and is associated with a significant risk of toxicities. Moreover, patients with higher-risk genetic abnormalities continue to experience poorer outcomes and lower survival. Recently, novel targeted therapies have been developed to increase efficacy and reduce toxicity.

Areas covered: Ibrutinib is an oral irreversible inhibitor of Bruton’s tyrosine kinase, a mediator of B-cell receptor signaling, which plays a vital role in various B-cell neoplasms. The drug has been approved for the treatment of several hematological malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma, where large trials have shown outcomes never seen before even in high-risk patients. The safety profile appeared furthermore favorable, even in elderly and unfit patients.

Expert opinion: Therapy with ibrutinib rarely provides MRD-negative complete remission; an indefinite maintenance is therefore needed, with the risk of developing adverse events (AE) or resistance resulting in treatment interruption or discontinuation. Novel, extremely promising, combination strategies, based on the association of ibrutinib with chemoimmunotherapy, anti-CD20 monoclonal antibody or other targeted agents, are currently being investigated, with the goal of achieving greater depth of remission, especially MRD-negativity, and removing the need for indefinite treatment.

KEYWORDS:

• BTK inhibitor
• chemoimmunotherapy
• chronic lymphocytic leukemia
• ibrutinib
• minimal residual disease
• targeted therapies

Article highlights

• Constitutive activation of BCR signal transduction cascade is crucial for tumor proliferation and survival; ibrutinib is a first in class inhibitor of Bruton’s tyrosine kinase (BTK), a mediator of BCR receptor signaling, which exerts its action by irreversibly binding to the activation site of the BTK enzyme at the cysteine-481 amino acid.

• Ibrutinib is orally administrated and is metabolized primarily via CYP3A4. The drug is mainly eliminated by the liver; renal is minimal.

• Large phase Ib/II and randomized trials led to the FDA approval of ibrutinib, with a daily dose of 420 mg, both for untreated or R/R CLL.

• Results of ibrutinib in clinical practice are substantially comparable to clinical trials; otherwise, incidence of adverse events and discontinuation rate seems much higher in this setting.

• Most adverse events with ibrutinib are grades 1–2 and self-limited, and do not require therapy interruption. Bleeding and atrial fibrillation are probably caused by ibrutinib off target effects.

• Ibrutinib has allowed to rescue high-risk patients with very limited treatment options. However, the achievement of deep remission is still an unmet need, and extremely promising combination strategies are being explored, with the aim to improve response quality and discontinue therapy maintenance.

Declaration of interest

A Tedeschi received honoraria and participated to advisory board from Janssen, Abbvie, Beigene and Sunesis. M Montillo received honoraria and participated to advisory board from Verastem, Abbvie, Janssen, AstraZeneca, Roche, and Gilead. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has received research funding and honoraria from Pharmacyclics which makes ibrutinib. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.