Bruton’s tyrosine kinase inhibitors in primary central nervous system lymphoma—evaluation of anti-tumor efficacy and brain distribution

Abstract

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive lymphoma confined to central nervous system. Current treatments including surgery, chemotherapy and whole-brain radiotherapy often fail to achieve satisfactory effect, especially in elderly. As a regimen in targeted therapy, Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been tested in several clinical trials against PCNSL, offering hope for patients unfit for chemotherapy. We aim to evaluate and compare the anti-PCNSL ability of three different BTK inhibitors, ibrutinib, zanubrutinib and tirabrutinib, providing direct evidence for the targeted therapy of PCNSL.Methods: Retrospective study was done on patients who received ibrutinib-based therapy in our hospital.Cerebrospinal fluid (CSF) from one patient was collected to measure the concentration of ibrutinib.Inhibition assay and apoptosis assay were done on lymphoma cells to determine the anti-tumoral effects of three inhibitors. Pharmacokinetic study was conducted to evaluate their ability in penetrating blood brain barrier and distributing in brain.Results: In retrospective study, we found three patients with PCNSL who had good clinical response to ibrutinib-based therapy (2 complete remission, 1 partial remission), which further support the use of BTK inhibitors in PCNSL. In vitro studies show that ibrutinib has the best anti-tumoral ability among three inhibitors. In vivo study on pharmacokinetic profiles indicate that both ibrutinib and tirabrutinib are good in distributing in brain parenchyma. Conclusions:In conclusion, our study results suggest that BTK inhibitors can be promising candidates for PCNSL treatment, preferring the use of ibrutinib and tirabrutinib as anti-PCNSL agents among the three inhibitors.

An experience with ibrutinib monotherapy for Richter’s syndrome isolated in the central nervous system

“…Although the prognosis of RS remains poor, especially with CNS involvement, 3 ibrutinib has been found to be an effective treatment. 4,5 Furthermore, ibrutinib is effective and safe for the treatment of primary CNS lymphoma [6][7][8] and mantle cell lymphoma with CNS involvement. 9,10 The permeability of ibrutinib across the blood-brain barrier was determined by measuring its concentration in the cerebrospinal fluid (CSF) of patients.…”

“…9,10 The permeability of ibrutinib across the blood-brain barrier was determined by measuring its concentration in the cerebrospinal fluid (CSF) of patients. [6][7][8][9][10] The unbound brain-to-plasma concentration ratio of ibrutinib, a pharmacokinetic parameter, was reported to be 9.8% in rats. 8 A CSF-to-plasma ibrutinib concentration ratio of 1-7% has been reported in patients.…”

“…3 Despite this poor disease prognosis, the Bruton's tyrosine kinase inhibitor ibrutinib has been reported to be effective in treating patients with RS, 4,5 and the blood-brain barrier permeability of ibrutinib has been recently demonstrated. [6][7][8][9][10] However, the efficacy of ibrutinib in patients with RS presenting with CNS involvement remains unclear.…”

Evidence-based expert consensus on the management of primary central nervous system lymphoma in China

“…The majority of AEs were hematological toxicities, which occurred more with combined ibrutinib and chemotherapy [82,84]. Only one non-randomized study has been reported for another BTKi, tirabrutinib in the treatment of refractory/relapsed (R/R) PCNSL (n = 44) [85].…”

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

“…In vitro and in vivo studies demonstrated that Ibrutinib was more effective than Zanubrutinib and Tirabrutinib for the treatment of PCNSL with an ideal pharmacokinetic property in brain distribution. 96 Ibrutinib monotherapy exhibits impressive clinical activity and safety with the ORR reaching 77% in a phase I clinical trial. 97 Similar positive results were obtained in another phase I trial.…”