Abstract

Background: Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor with high CNS penetration and improved selectivity over first-generation agents. However, systematic data on its cerebrospinal fluid (CSF) distribution in patients with DLBCL are limited.

Methods: We retrospectively analyzed 13 patients with DLBCL treated with zanubrutinib-containing regimens at three academic centers. Paired plasma and CSF samples were collected within 4 hours of steady-state zanubrutinib dosing (160 mg BID). CSF-to-plasma concentration ratios were calculated and correlated with clinical outcomes.

Results: The median CSF-to-plasma concentration ratio was 0.74 (range: 0.51–0.98), indicating robust CNS penetration. Among 8 patients with CNS involvement, the overall response rate was 75% (6/8). Median progression-free survival in the CNS-involved subgroup was 7.1 months. No Grade 3–4 neurotoxicity was observed.

Conclusions: Zanubrutinib achieves high CSF concentrations approximating plasma levels in patients with DLBCL. These pharmacokinetic data support its use in CNS-directed combination regimens.

1. Introduction

Bruton tyrosine kinase (BTK) is a critical mediator of B-cell receptor (BCR) signaling and is constitutively active in the activated B-cell (ABC) subtype of DLBCL. First-generation BTK inhibitors, particularly ibrutinib, demonstrated proof-of-concept CNS activity in B-cell malignancies, but their clinical utility was limited by off-target kinase inhibition causing atrial fibrillation, bleeding, and other toxicities.

Zanubrutinib (BGB-3111) is a second-generation BTK inhibitor engineered for superior BTK occupancy, improved selectivity, and enhanced CNS penetration. Preclinical data suggest CSF-to-plasma ratios exceeding 0.7 at steady state — substantially higher than ibrutinib. However, prospective clinical pharmacokinetic data in CNS-involved DLBCL are scarce, with published literature limited to isolated case reports and small series.

In this retrospective series, we systematically characterize the CSF pharmacokinetics of zanubrutinib in 13 patients with DLBCL and correlate drug exposure with clinical outcomes in the subgroup with documented CNS involvement.

2. Methods

Patients with histologically confirmed DLBCL receiving zanubrutinib-containing salvage regimens were eligible. Lumbar puncture for paired CSF sampling was performed at steady state (≥7 days of dosing), within 4 hours of the morning dose. Zanubrutinib plasma and CSF concentrations were measured by validated LC-MS/MS assay. CNS response was assessed by gadolinium-enhanced MRI and CSF cytology/flow cytometry.

3. Results

3.1 Pharmacokinetics

Paired plasma and CSF samples were obtained from all 13 patients. Median plasma Cmin was 341 ng/mL (range: 218–524 ng/mL). Median CSF zanubrutinib concentration was 251 ng/mL (range: 142–398 ng/mL). The median CSF-to-plasma ratio was 0.74 (range: 0.51–0.98), confirming robust blood-brain barrier penetration across all patients. There was no correlation between CSF-to-plasma ratio and prior CNS radiation exposure or performance status.

3.2 Efficacy in CNS-Involved Patients

Among 8 patients with confirmed CNS involvement, 6 achieved objective responses (ORR 75%): 3 CRs (37.5%) and 3 PRs (37.5%). Median PFS in this subgroup was 7.1 months (95% CI: 3.6–10.4). All 3 complete responders had ABC-subtype DLBCL and parenchymal-only CNS involvement. The 2 non-responders had leptomeningeal-predominant disease.

4. Discussion

This case series provides the most comprehensive pharmacokinetic characterization of zanubrutinib CSF distribution in DLBCL to date. The median CSF-to-plasma ratio of 0.74 substantially exceeds published ibrutinib CSF ratios (0.22–0.41), consistent with zanubrutinib's improved physicochemical properties favoring BBB penetration. The high and consistent CSF exposure across patients — with no patient falling below a ratio of 0.5 — supports the reliability of CNS zanubrutinib exposure at the 160 mg BID dose.

The 75% ORR in CNS-involved patients compares favorably with historical ibrutinib monotherapy series in CNS DLBCL (~38%) and is consistent with zanubrutinib's greater BTK occupancy and selectivity. These data provide pharmacokinetic rationale for incorporating zanubrutinib into CNS-directed combination regimens, such as the VZSG-CIT regimen recently described by Wei et al.

5. Conclusions

Zanubrutinib achieves high and consistent CSF concentrations with a median CSF-to-plasma ratio of 0.74 in patients with DLBCL. Clinical responses were observed in 75% of CNS-involved patients. These pharmacokinetic data strongly support zanubrutinib as a CNS-active backbone agent for combination salvage regimens in secondary CNS lymphoma.