BTK Inhibitors for the Treatment of Mantle Cell Lymphoma—Current Status and Perspectives

The introduction of Bruton’s tyrosine kinase inhibitors (BTKis) has significantly improved prognosis in the treatment of MCL. BTK inhibitors have demonstrated strong activity in the treatment of relapsed/refractory patients with mantle cell lymphoma (MCL), and several trials indicate that they also have potential as first-line treatment. Furthermore, combining BTKis with immunochemotherapy has enabled time-limited therapy as an alternative for continuous treatment with BTK inhibitors alone. In 2013, ibrutinib became the first BTK inhibitor to be approved by the FDA for previously treated MCL. The TRIANGLE study found ibrutinib to improve the efficacy of standard immunochemotherapy and reduce the need for autologous stem cell transplantation (ASCT) in younger patients; however, its findings do not conclusively confirm whether ASCT enhanced the activity of the ibrutinib-containing regimen in treatment-naïve patients. The second-generation covalent, irreversible BTK inhibitors acalabrutinib and zanubrutinib demonstrate greater selectivity and better pharmacological characteristics than ibrutinib. The FDA has approved acalabrutinib and zanubrutinib as single drugs for the treatment of R/R patients with MCL who have received at least one prior therapy. Acalabrutinib combined with bendamustine and rituximab was also approved for TN MCL unsuitable for ASCT. Pirtobrutinib, a first-in-class noncovalent reversible BTK inhibitor, was approved for the treatment of R/R MCL patients, including those resistant to covalent BTK inhibitors. Several other covalent and noncovalent BTK inhibitors are currently under investigation in MCL. Finally, BTK degraders have entered early clinical trials in B-cell lymphoid malignancies, and some of them in MCL.