Use of BTK inhibitors with focus on ibrutinib in mantle cell lymphoma: An expert panel opinion statement

Abstract

The introduction of Bruton's tyrosine kinase (BTK) inhibitors transformed the management of patients with mantle cell lymphoma (MCL). Ibrutinib, the first-inclass BTK inhibitor is now approved in more than 80 countries and there are over 20 new BTK inhibitors in development. In addition, novel agents show potential clinical activity (alone and in combination) and are in the approval phase and/or being studied in ongoing clinical trials. How does the practicing clinician decide on the optimal therapeutic strategy for this highly heterogenous disease? In July 2020 a group of experts from Italy, convened a meeting to address and provide clarification on a series of outstanding issues in the treatment of MCL with the view of providing clinical guidance on its management. This expert opinion statement represents the panel's collective analysis, evaluation, and recommendations and is made up of a series of questions and answers (in the form of a review of the pertinent literature) designed to replicate those posed by practicing clinicians in Italy but which are applicable to clinical settings worldwide.

Survival Outcomes of Patients with Mantle Cell Lymphoma: A Retrospective, 15-Year, Real-Life Study

“…Despite promising results, frequent relapses and an increasingly shorter duration of response have been reported after each line of therapy [ 11 , 12 , 13 , 14 , 15 ]. Ibrutinib represents the most effective novel agent and has shown prolonged efficacy with manageable toxicity [ 19 , 20 , 21 , 22 , 23 ]. In a long-term follow-up analysis across three clinical trials, median PFS was 12.8 months; interestingly, the longest PFS was achieved for patients receiving ibrutinib as second-line therapy [ 23 ].…”

“…Ibrutinib is an oral, covalent BTK inhibitor, which demonstrated encouraging long-term efficacy in several NHL subtypes, including R/R MCL [ 19 , 20 , 21 , 22 , 23 ]. Ibrutinib showed prolonged progression-free survival (PFS) and OS with mild toxicity, especially as a second-line regimen; however, survival was reduced for patients with chemo-refractory MCL and/or TP53 mutations [ 24 , 25 ].…”

Unmet needs in relapsed/refractory mantle cell lymphoma after failure of covalent Bruton's tyrosine kinase inhibitors: An Italian scenario

“…Marco Ladetto 2 Maurizio Martelli 3 Carlo Visco 4 Francesco Zaja 5 Emanuele Guardalben 6 Pier Luigi Zinzani…”

B-cell receptor signaling activity identifies patients with mantle cell lymphoma at higher risk of progression

“…Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase (BTK), a key protein on the route of the BCR signaling, which binds covalently to the active site of BTK and inhibits kinase’s enzymatic activity and downstream signaling 18 . In MCL, ibrutinib has significantly improved patients’ long-term outcome and overall response among relapsed-refractory patients 19 , 20 . Despite the remarkable activity of ibrutinib and other BTK inhibitors (BTKi), treatment results are poor in a proportion of patients 19 , 21 – 23 and several mechanisms of intrinsic or adaptive resistance to these selective inhibitors, including activation of compensatory pathways and acquisition of mutations, have been described 24 – 26 .…”

“…In MCL, ibrutinib has significantly improved patients’ long-term outcome and overall response among relapsed-refractory patients 19 , 20 . Despite the remarkable activity of ibrutinib and other BTK inhibitors (BTKi), treatment results are poor in a proportion of patients 19 , 21 – 23 and several mechanisms of intrinsic or adaptive resistance to these selective inhibitors, including activation of compensatory pathways and acquisition of mutations, have been described 24 – 26 . Thereby, identifying mechanisms of resistance/relapse to BTKi therapy is critically challenging.…”