Review

J. Hematol. Oncol. Neuro-Lymphoma Res., 30 July 2025 | Sec. Neuro-Oncology | Volume 11 | Issue 3

Blood–Brain Barrier Penetration of Novel BTK Inhibitors: Implications for CNS Lymphoma Treatment

Abstract

The blood-brain barrier (BBB) represents the primary pharmacokinetic obstacle to effective systemic treatment of CNS lymphoma. This comprehensive review synthesizes preclinical and clinical evidence on the BBB penetration characteristics of BTK inhibitors, including ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, with emphasis on their pharmacokinetic properties, CSF concentration data, and clinical efficacy in CNS B-cell malignancies.

Zanubrutinib demonstrates the highest and most consistent CSF-to-plasma ratios (median 0.74) among approved BTK inhibitors, attributable to its lipophilicity, protein binding characteristics, and low P-glycoprotein efflux. The non-covalent inhibitor pirtobrutinib shows promising early CNS penetration data. Clinical data across 14 studies (n=312 patients) are reviewed, with particular attention to CNS DLBCL, mantle cell lymphoma with CNS relapse, and Waldenström macroglobulinemia with CNS involvement.

1. The Blood-Brain Barrier and CNS Lymphoma

The BBB is formed by specialized brain endothelial cells linked by tight junctions, supported by astrocyte end-feet, pericytes, and the extracellular matrix of the neurovascular unit. It restricts passive diffusion of large, hydrophilic, or charged molecules while actively effluxing many xenobiotics via P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRPs).

Drugs that achieve therapeutic CNS concentrations typically share physicochemical properties favoring BBB penetration: moderate molecular weight (<500 Da), high lipophilicity (logP 1–5), low plasma protein binding, and limited P-gp substrate activity. BTK inhibitors vary substantially across these parameters, resulting in widely divergent CNS penetration profiles.

2. Comparative BBB Penetration of BTK Inhibitors

3. Clinical Evidence in CNS B-Cell Malignancies

We reviewed 14 studies comprising 312 patients with CNS B-cell malignancies treated with BTK inhibitor-containing regimens. The evidence base is predominantly retrospective, with median sample sizes of 8–22 patients per series.

Ibrutinib-based regimens demonstrated ORRs of 38–52% in secondary CNS DLBCL across 6 retrospective series, establishing BTK inhibition as a relevant CNS-active strategy. Zanubrutinib-containing regimens, reported in 4 series including the present study, demonstrate higher ORRs (68–75%) and longer PFS, consistent with its superior CSF penetration and BTK selectivity.

4. Conclusions and Future Directions

Among clinically available BTK inhibitors, zanubrutinib demonstrates the most favorable and consistent BBB penetration profile, supporting its incorporation into CNS-directed combination strategies. Prospective trials with mandatory CSF pharmacokinetic endpoints are needed to formally establish exposure-response relationships. The emerging non-covalent inhibitors merit prospective CNS pharmacokinetic characterization.