Case Report

Front. Oncol., 21 July 2025 | Sec. Immunotherapy & Biologics | Volume 15

Glofitamab Intrathecal Administration in Richter Transformation With Isolated CNS Relapse: Feasibility, Immune Activation, and Clinical Response

Abstract

Richter transformation (RT) to DLBCL with isolated CNS relapse represents an exceedingly rare and therapeutically challenging scenario. We report the case of a 67-year-old man with CLL undergoing RT to DLBCL who relapsed with isolated leptomeningeal and parenchymal CNS disease after two prior lines of systemic therapy, including venetoclax and obinutuzumab.

The patient received intrathecal (IT) glofitamab (0.5 mg per cycle) combined with systemic venetoclax and zanubrutinib. CSF flow cytometry demonstrated robust T-cell expansion (CD8+ T-cell increase from 4% to 38% of CSF lymphocytes) 72 hours post-IT glofitamab administration. The patient achieved complete CNS response after 4 cycles, confirmed by gadolinium-enhanced MRI and negative CSF cytology. Response lasted 9.4 months before systemic Richter progression.

This case demonstrates the feasibility and CNS immune activation potential of intrathecal glofitamab in isolated CNS Richter transformation, supporting its further evaluation in this rare but lethal disease manifestation.

Case Presentation

A 67-year-old male with a 4-year history of CLL (IGHV-unmutated, del(17p), TP53-mutated) was referred for progressive neurological symptoms including headache, diplopia, and left-sided weakness. He had received ibrutinib (discontinued due to atrial fibrillation), then venetoclax plus obinutuzumab (V+O) achieving partial response. MRI brain revealed multiple enhancing parenchymal lesions (largest 2.1 cm, right temporal lobe) and meningeal enhancement. CSF cytology confirmed CD20+ large B-cell lymphoma consistent with Richter transformation, DLBCL phenotype. PET-CT showed no systemic disease, confirming isolated CNS RT-DLBCL.

Given prior venetoclax/anti-CD20 exposure and isolated CNS disease, systemic regimen intensification was deemed unlikely to provide CNS benefit. After multidisciplinary discussion and institutional review board approval, the patient consented to IT glofitamab as part of a salvage regimen including systemic venetoclax re-challenge (400 mg daily) and zanubrutinib (160 mg BID).

Treatment and Response

IT glofitamab 0.5 mg was administered via lumbar puncture on Day 3 of each 21-day cycle, diluted in 3 mL preservative-free normal saline. Obinutuzumab 1000 mg IV was administered 7 days prior to Cycle 1 Day 1 as CRS pre-medication. IV glofitamab (step-up: 2.5 → 10 → 30 mg) was not administered given the goal of maximizing CNS concentration via direct IT delivery and minimizing systemic immunosuppression.

CSF examination 72 hours after IT glofitamab Cycle 1 demonstrated a striking increase in CD3+CD8+ T cells (from 4% to 38% of CSF lymphocytes by flow cytometry), with concurrent decrease in CD20+ large B cells (from 62% to 11%). Cytokine analysis showed CSF IL-6 elevation (peak 84 pg/mL, Grade 1 CRS), resolving without corticosteroids.

After 4 cycles, gadolinium-enhanced MRI showed complete resolution of all parenchymal lesions and meningeal enhancement. CSF cytology and flow cytometry were negative for malignant cells. ECOG PS improved from 2 to 1. Response lasted 9.4 months; systemic Richter progression (non-CNS) was detected at Month 10 by PET-CT.

Discussion

To our knowledge, this represents the first reported case of IT glofitamab in RT-DLBCL with isolated CNS relapse. The striking CSF T-cell expansion (10-fold CD8+ T-cell increase within 72 hours) provides direct cellular evidence of bispecific antibody-mediated immune activation in the CNS compartment, supporting the immunological rationale for IT delivery.

Glofitamab's mechanism — engaging CD20 on tumor cells and CD3 on T cells — is particularly suited for intrathecal administration because the CNS compartment contains resident T cells capable of activation, and the enclosed CSF space may concentrate the bispecific antibody in proximity to leptomeningeal and parenchymal tumor cells. The very low dose used (0.5 mg IT vs 30 mg IV at maintenance) suggests that direct compartmental delivery may be highly efficient.

The eventual systemic RT progression despite sustained CNS CR underscores that isolated CNS RT-DLBCL likely represents a CNS sanctuary phenomenon rather than a separate clone, and that effective CNS therapy alone does not prevent systemic relapse in this context.