Bruton’s tyrosine kinase inhibitors in B-cell lymphoma: current experience and future perspectives

ABSTRACT

Introduction: The Bruton tyrosine kinase (BTK) is a central hub in the B cell receptor (BCR) pathway and strongly influences B cell maturation, differentiation and proliferation. Not surprisingly, BTK plays an essential role in the pathogenesis of various B cell lymphomas. Inhibitors of BTK have broadened our therapeutic options in several B cell lymphomas and already are an integral element in the treatment of Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström’s marcoglobulinemia. Several second generation BTK inhibitors are in clinical development and might further improve tolerability and efficacy of therapy in advanced stage CLL and MCL.

Areas covered: This review illustrates the mechanism of action of BTK inhibitors and provides a comprehensive summary of key clinical trials in the development of BTK inhibitors. Characteristics of second generation BTK-inhibitors are described.

Expert opinion: With accumulation of clinical experience after drug approval, longer patient follow-up and larger numbers of treated patients, future development will focus on the identification of intelligent treatment combinations. Individual selection of patients with distinct biologically properties might guide treatment decisions. While BTK inhibitors are moving to earlier treatment lines, the incorporation of these drugs into a comprehensive therapeutic strategy is still difficult to date.

KEYWORDS:

• Bruton’s tyrosine kinase (BTK)
• chronic lymphocytic leukaemia (CLL)
• ibrutinib
• mantle cell lymphoma (MCL)

Article highlights

• BTK inhibitors interfere with the BCR signalling pathway and thereby disrupt signals important for proliferation, maturation, differentiation, apoptosis and cell migration in both normal and neoplastic B cells

• As a class effect of drugs interfering with the BCR pathway, a transient lymphocytosis can frequently be observed and should not be judged as treatment failure

• The first in class BTK inhibitor shows major activity especially in high risk CLL

• In MCL, duration of response to ibrutinib monotherapy is significantly shorter in aggressive MCL and in advanced therapy lines

• Ibrutinib has high activity in Waldenströms macrglobulinemia also in patients refractory to rituximab

• Second generation BTK inhibitors might improve tolerability due to fewer off-target effects

This box summarizes key points contained in the article.

Declaration of interest

M. Dreyling has received speaker’s honorarium and served on the scientific advisory board for Janssen. 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.

Additional information

Funding

This paper was not funded.