Abstract
Ibrutinib is the first Bruton’s tyrosine kinase (BTK) inhibitor, which showed significant clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients regardless of cytogenetic risk factors. Recent results of phase III clinical trials in treatment-naïve CLL patients shift the importance of the agent to frontline therapy. Nevertheless, beside its clinical efficacy, ibrutinib possesses some off-target activity resulting in ibrutinib-characteristic adverse events including bleeding diathesis and arrhythmias. Furthermore, acquired and primary resistance to the drug have been described. As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors’ resistance and discuss the post-ibrutinib treatment options.
Highlights
Chronic lymphocytic leukemia (CLL) is an incurable clonal proliferation of smallCD5/CD19-positive lymphocytes accumulating in blood, bone marrow and lymphoid tissues accounting for approximately 25% of all leukemias in Europe and North America [1,2]
The outcome of chronic lymphocytic leukemia (CLL) patients who are refractory or relapsed to immunochemotherapy changed with the development of novel agents inhibiting B cell receptor (BCR) signaling, e.g., Bruton’s tyrosine kinase (BTK)
Ibrutinib is relatively selective towards BTK; the compound has some off-target activity such as the inhibition of several other tyrosine kinases and their pathways, e.g., epidermal growth factor receptor (EGFR), interleukin-2-inducible T cell kinase (ITK), T cell X chromosome kinase (TXK)
Summary
Chronic lymphocytic leukemia (CLL) is an incurable clonal proliferation of small. CD5/CD19-positive lymphocytes accumulating in blood, bone marrow and lymphoid tissues accounting for approximately 25% of all leukemias in Europe and North America [1,2]. The disease has a heterogenous clinical course, and numerous studies aimed at identifying novel prognostic and predictive factors are being intensively performed. Immunochemotherapy tailored to patients’ fitness has so far remained the backbone of frontline CLL treatment in the majority of patients, the development of novel selective compounds targeting the B cell receptor (BCR), along with increasing knowledge of predictive factors, have improved patients’ prognosis [3,4]. The outcome of CLL patients who are refractory or relapsed to immunochemotherapy changed with the development of novel agents inhibiting BCR signaling, e.g., Bruton’s tyrosine kinase (BTK). Inhibitor ibrutinib and the phosphoinositide 3-kinase (PI3K) delta inhibitor idelalisib [4,13,14] Both compounds presented remarkably high activity in CLL, including patients with p53 dysfunction [13,14,15]. We present the most important findings regarding the resistance mechanisms to ibrutinib, reasons of therapy discontinuation, and put special emphasis on potential strategies and alternative compounds with the potential to overcome these clinical issues
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