Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

Abstract

Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%–26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%–51% of patients, and is mainly grade 1–2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

“…As such, it is essential to provide optimal management to achieve the best possible outcomes for patients [110,111]. The most common reason for discontinuing ibrutinib is toxicity, particularly the AEs specific for this group of drugs, such as atrial fibrillation (AF), bleeding events, arthralgias, rash, diarrhea, and cytopenias [112]. Ibrutinib discontinuation caused by AEs, mainly AF, arthralgias, rash, diarrhea, and bleeding events, was observed in 4-26%.…”

All Bruton’s tyrosine kinase inhibitors have similar efficacy and risks: No

“…Bruton's tyrosine kinase (BTK) is a key molecule in B-cell signal transduction. 4 Blocking this enzyme does not induce B-cell depletion as in ocrelizumab-treated patients but inhibits the differentiation and the survival of B-cells and myeloid cells. 4 This results in a reduced and modified B-cell response.…”

“… 2 , 3 However, given the relatively small numbers enrolled and brief durations of these studies, we expect that in Phase III trials and clinical practice, selectivity will lead to differential side effect profiles among therapies, as we have seen with approved BTKIs. 1 , 4 …”

“…Secondary bleeding, for example, is thought to arise from both BTK and TEC family inhibition. 4 In a pooled analysis of studies of fenebrutinib in other diseases, bleeding or bruising was reported in 8%, although serious bleeding events were rare. 5 The mechanism for fungal infection is incompletely understood but may be due to effects of BTK inhibition on the innate immune system.…”

Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance

“…For example, there are analyses that suggest that ibrutinib-associated atrial fibrillation is caused by the binding to ERBB2/HER2 and C-terminal Src kinases (CSK), which also harbor a BTK inhibitor-binding cysteine in their catalytic domain. 11 , 26 Binding to other off-target kinases is also thought to result in higher rates of rash (Epidermal growth factor (EGFR)), diarrhea (EGFR), and bleeding (TEC). 11 , 12 , 26 Contrary to ibrutinib, acalabrutinib does not inhibit other kinases with the conserved cysteine residue.…”