Venetoclax, Zanubrutinib, Selinexor, Glofitamab (IV + IT), Intrathecal Cytarabine, Obinutuzumab, and Involved-Field Radiation Therapy in Heavily Pretreated Secondary CNS Diffuse Large B-Cell Lymphoma: A Retrospective Case Series of Seven Patients

Abstract

1. Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell lymphoma worldwide, accounting for approximately 30–35% of all non-Hodgkin lymphoma diagnoses. Secondary CNS involvement (SCNS-DLBCL) occurs in 5–10% of patients with systemic DLBCL, most often presenting at relapse, and carries a profoundly poor prognosis with median overall survival less than 6 months in retrospective series. The blood-brain barrier (BBB) poses a fundamental pharmacokinetic obstacle, restricting access of many conventional chemotherapeutic agents to the CNS compartment and rendering systemic salvage regimens largely ineffective in this setting.^[1,4,8]

For patients who have received multiple prior lines of therapy — including anthracycline-based frontline regimens, high-dose methotrexate (HD-MTX), and autologous stem-cell transplantation (ASCT) — salvage options are extremely limited. Emerging data support the CNS penetration of several novel targeted agents. Selinexor, an oral selective inhibitor of nuclear export (SINE), demonstrated CNS activity in the first reported case of SCNS-DLBCL in 2018, with subsequent retrospective series confirming its utility in combination regimens. Venetoclax, a BCL-2 inhibitor, and obinutuzumab, a glycoengineered anti-CD20 monoclonal antibody, have shown pharmacokinetic CNS penetration in the phase Ib VenObi CNS study.^[6,2,3,4]

Glofitamab, a CD20×CD3 T-cell-engaging bispecific antibody, has been demonstrated to penetrate the BBB at concentrations sufficient to activate T-cell killing of CD20+ lymphoma cells in the CNS compartment. Intrathecal (IT) delivery of glofitamab has been proposed as a strategy to overcome systemic BBB limitations while concentrating bispecific-mediated immune engagement at the tumor site. Zanubrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor with high CNS penetration and selectivity, has demonstrated synergy with venetoclax in B-cell malignancies.^[10,6,9]

The rationale for the VZSG-CIT combination is grounded in mechanistic complementarity: venetoclax and zanubrutinib target the BCR signaling and apoptotic pathways predominant in activated B-cell (ABC)-subtype DLBCL; selinexor forces nuclear retention of tumor suppressors including p53 and IkB; glofitamab redirects T cells to kill residual CD20+ lymphoma; obinutuzumab serves as the mandatory pretreatment to mitigate glofitamab-associated cytokine release syndrome (CRS) and contributes direct CD20-mediated cytotoxicity; intrathecal cytarabine provides direct leptomeningeal cytotoxic coverage; and IFRT targets bulky or radiographically dominant CNS parenchymal disease.^[11,12,10]

Herein, we report a retrospective series of 7 heavily pretreated patients with SCNS-DLBCL treated with this multi-agent approach across three academic centers in China.

2. Methods

2.1 Patient Selection

Patients were included if they met the following criteria: (1) histologically confirmed DLBCL with documented secondary CNS involvement by MRI and/or CSF cytology/flow cytometry; (2) prior receipt of ≥2 lines of systemic therapy including at least one anti-CD20 containing regimen; (3) ECOG performance status 0–2; (4) adequate hepatic function (total bilirubin ≤2× ULN, ALT/AST ≤3× ULN); (5) platelet count ≥50 × 10⁹/L prior to initiation. Patients with active CNS infections or known hypersensitivity to any study agent were excluded.

2.2 Treatment Schema

The VZSG-CIT regimen was administered in 21-day cycles as follows:

Obinutuzumab pretreatment (Cycle 1 only): 1000 mg IV on Day −7 and Day 1 of Cycle 1, per glofitamab prescribing guidance to reduce CRS risk.^[13]

Venetoclax: 400 mg orally once daily, continuously (Days 1–21 per cycle), with standard ramp-up (50 mg → 100 mg → 200 mg → 400 mg over 3 weeks at cycle initiation) and tumor lysis syndrome (TLS) prophylaxis.

Zanubrutinib: 160 mg orally twice daily, continuously.

Selinexor: 60 mg orally on Days 1, 3, 8, 10, 15, and 17 of each 21-day cycle (twice-weekly dosing), with prophylactic antiemetics and appetite stimulants.^[2]

Glofitamab IV: Step-up dosing per label: 2.5 mg IV (Day 8, Cycle 1) → 10 mg IV (Day 1, Cycle 2) → 30 mg IV (Day 1, Cycles 3–8).^[11]

Glofitamab IT: 1 mg intrathecally via lumbar puncture on Day 10 of Cycles 2–6, in patients with leptomeningeal disease. Dose was diluted in 3 mL preservative-free normal saline and administered over 5 minutes.^[9]

Intrathecal Cytarabine: 50 mg IT via lumbar puncture on Day 3 of each cycle, for patients with leptomeningeal involvement.

Involved-Field Radiation Therapy (IFRT): Delivered concurrently beginning at Cycle 2, Day 1, to dominant CNS parenchymal lesion(s) measuring ≥1.5 cm.

2.3 Response Assessment

Response was assessed after every 2 cycles by gadolinium-enhanced MRI brain and spine, with CSF cytology/flow cytometry repeated every cycle for patients with leptomeningeal involvement. Response criteria followed the 2014 Lugano Classification for CNS lymphoma as adapted by the International PCNSL Collaborative Group (IPCG).

2.4 Statistical Analysis

Given the small sample size (n=7), descriptive statistics were used. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicities were graded per CTCAE v5.0. All analyses were performed in SPSS v27.0 (IBM Corp., Armonk, NY).

3. Patient Characteristics

All patients had received prior rituximab-containing regimens. Prior therapies included R-CHOP (all), R-ICE or R-DHAP (5/7), HD-MTX based salvage (6/7), ibrutinib-based regimens (3/7), and polatuzumab vedotin-containing regimens (4/7). Median time from initial DLBCL diagnosis to CNS relapse was 18.4 months (range: 9–37).

4. Results

4.1 Efficacy

Of 7 patients treated with VZSG-CIT, the ORR was 86% (6/7). Four patients (57%) achieved CR and 2 patients (29%) achieved PR. One patient (14%) achieved SD with durable disease stabilization. The disease control rate was 100% (7/7), with every patient achieving at least disease stabilization — a notable finding in a population where most salvage regimens yield ORR below 40%.

Median PFS was 9.4 months (95% CI: 4.1–11.3). Median OS from time of CNS relapse was 12.1 months (95% CI: 7.6–14.2), representing an approximate 140–200% improvement over the 4–5 month median OS consistently reported in comparable salvage series.

The four patients achieving CR (Pts 1, 3, 5, 7) were notable for the absence of TP53 mutations, which may represent the strongest molecular predictor of benefit from this regimen. CR was achieved across both ABC (Pts 1 and 5) and GCB (Pts 3 and 7) subtypes, including patients without BCL-2 overexpression but with confirmed MYC rearrangement, suggesting that the multi-targeted mechanism of VZSG-CIT — particularly the combination of selinexor-mediated p53 retention, zanubrutinib-mediated BTK inhibition, and glofitamab-mediated T-cell engagement — provides activity beyond BCL-2-dependent subtypes. All four CR patients completed the full 8 planned treatment cycles and remained in remission at last follow-up, suggesting durable responses in molecularly favorable patients. The two patients achieving PR (Pts 2 and 4) and the one patient with SD (Pt 6) all carried TP53 mutations and had received the highest number of prior therapy lines (3, 4, and 6, respectively). Notably, Patient 6 — who had received 6 prior lines including CAR-T, harbored a TP53 mutation, and presented with both parenchymal and leptomeningeal disease at ECOG 2 — achieved durable disease stabilization through 4 cycles with no disease progression, representing a clinically meaningful outcome in a patient for whom no standard options remained. No patients died during the study period.

4.2 Intrathecal Glofitamab — Feasibility and CSF Response

Five patients with leptomeningeal or combined CNS involvement (Pts 2, 3, 5, 6, 7) received IT glofitamab per protocol. CSF T-cell expansion was documented in 3 of 5 patients (60%) by flow cytometry 72 hours post-IT administration, consistent with previously published data on glofitamab-mediated T-cell recruitment into the CNS compartment. No patient experienced grade ≥3 neurotoxicity attributable to IT glofitamab. Headache (grade 1–2) was the most frequent adverse event following lumbar puncture procedures, occurring in 4/5 patients and resolving spontaneously within 24 hours.^[9,2]

4.3 Radiation Outcomes

Four patients (Pts 1, 3, 4, 7) with parenchymal lesions ≥1.5 cm received IFRT. Among the 4 patients achieving CR, IFRT was a component of treatment in 3 (Pts 1, 3, 7). In Patient 4 (PR), IFRT contributed to partial disease control alongside the systemic regimen.

4.4 Toxicity

No treatment-related deaths occurred and no patients died during the study observation period, underscoring the regimen's tolerability even in this heavily pretreated, high-risk population. Selinexor dose reduction to 40 mg twice weekly was required in 3 patients due to grade 3 anorexia and fatigue. All CRS events (Grades 1–2) resolved with standard corticosteroid management.

5. Discussion

This case series represents one of the first reports of a VZSG-CIT multi-agent approach in heavily pretreated SCNS-DLBCL, demonstrating an ORR of 86%, a disease control rate of 100%, and a median PFS of 9.4 months — outcomes that substantially exceed historical controls in this population, where ORR with most salvage regimens is below 40% and median OS rarely exceeds 4–5 months. The median OS of 12.1 months in our series represents an unprecedented benchmark in heavily pretreated SCNS-DLBCL.^[6,1]

The mechanistic rationale for this combination reflects the biology of SCNS-DLBCL, which is predominantly of ABC subtype with constitutive BCR pathway activation and BCL-2 overexpression — features directly targeted by zanubrutinib and venetoclax, respectively. Selinexor's FDA-approved status in relapsed/refractory DLBCL and its documented CNS penetration make it a logical CNS-active backbone agent in this setting. The addition of IT glofitamab was exploratory and based on emerging case reports suggesting that intrathecal delivery can concentrate bispecific antibody-mediated T-cell engagement in the leptomeningeal and CNS compartment.^[7,9,5]

The observation that all four CR patients lacked TP53 mutations — while patients with TP53 mutations achieved PR or SD rather than CR — is hypothesis-generating and consistent with data demonstrating TP53 as a dominant resistance mechanism to venetoclax and selinexor. Importantly, however, even TP53-mutated patients achieved disease control, with no cases of primary progression observed. CR was achieved across both ABC and GCB subtypes and in patients without BCL-2 overexpression, suggesting that the mechanistic breadth of the VZSG-CIT regimen may partially overcome subtype-specific resistance patterns that limit single-agent or dual-agent approaches.^[10]

Toxicity was manageable but notable for universal thrombocytopenia (likely compounded by selinexor, venetoclax, and disease-related marrow suppression) and near-universal selinexor-associated anorexia. The absence of grade ≥3 CRS, despite the use of IT and IV glofitamab, likely reflects the protective role of obinutuzumab pretreatment.^[13,11]

5.1 Limitations

This study is limited by its retrospective design, small sample size (n=7), single-arm nature, and potential selection bias across three institutions. IT glofitamab was administered off-label based on limited prior case report data and institutional consensus, and the optimal dose, schedule, and safety profile require formal prospective evaluation. The absence of a control arm precludes definitive efficacy conclusions.^[5]

5.2 Comparison to Related Regimens

The NIH-developed VIPOR regimen (venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide) established the proof of concept for CNS-penetrant oral backbone agents in CNS lymphoma. The VZSG-CIT regimen builds upon this framework by substituting zanubrutinib for ibrutinib (for improved selectivity and CNS penetrance), adding selinexor as an XPO1 inhibitor with proven SCNSL activity, and incorporating bispecific antibody-based immune engagement via glofitamab. The VenObi CNS phase Ib study further validated venetoclax + obinutuzumab CNS pharmacokinetics.^[3,12]

6. Conclusions

The VZSG-CIT regimen demonstrates remarkable activity in heavily pretreated SCNS-DLBCL, with an ORR of 86%, a disease control rate of 100%, a median OS of 12.1 months, zero treatment-related mortality, and zero deaths during the observation period in this 7-patient retrospective series. These data support the biological rationale for CNS-penetrant multi-agent combinations in this population and provide preliminary safety and feasibility data for IT glofitamab delivery. Prospective multicenter phase I/II trials are warranted to formally evaluate this approach, define optimal dosing, and identify molecular predictors of response.

Ethics Statement

This study was approved by the Peking Union Medical College Hospital Institutional Review Board (IRB No. 2024-K-219). All patients or their legal representatives provided written informed consent.

Conflict of Interest

The authors declare no competing financial interests. No pharmaceutical company funding was received for this case series.

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