Zanubrutinib-Combined Therapy as Salvage or Bridge to CAR-T in Non-GCB DLBCL: A Multicenter Retr

07 Apr 20265 min read0 viewsJournal Feed

GIST

This retrospective multicenter study evaluated zanubrutinib-based combinations in 27 heavily treated patients with non-GCB DLBCL. The cohort had high-risk features, with the majority presenting elevated IPI scores (88.9%), high Ki-67 proliferation (85.2%), and prior lines of therapy ≥3 (74.1%).

The overall response rate reached 74.1%, with a partial response rate of 66.7%. Median follow-up was 36.6 months; median PFS was 10.6 months and median OS was 19.6 months.

Grade ≥3 hematologic toxicities were common, including neutropenia (85.1%) and thrombocytopenia (37%), while nonhematologic ≥3 events included hypokalemia (11.1%) and pulmonary infection (11.1%). No treatment-related deaths occurred.

Subgroup analyses by sex, age, and extranodal disease largely maintained an ORR >70%. Among 27 patients, 2 achieved CR and proceeded to autologous stem cell transplantation or lenalidomide maintenance.

Nineteen bridged to CD19 CAR-T therapy, while six received additional salvage chemotherapy. In the CAR-T cohort, ORR was 89.5% and CR 57.9%, with median PFS 14 months and median OS 27.7 months; CAR-T was associated with improved OS versus non-CAR-T (HR 0.21).

Clinical Editorial

Context and study design

The investigation focuses on a retrospective multicenter cohort of 27 patients with heavily treated, relapsed or refractory non-GCB DLBCL.
Participants received zanubrutinib in combination regimens between January 2021 and February 2024 at two Chinese centers: Shanghai Tongji Hospital and Zhejiang Second Affiliated Hospital.
Primary efficacy endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS); safety assessments tracked adverse events, emphasizing grade 3 or higher hematologic and nonhematologic toxicities.

Patient characteristics and baseline risk

A substantial majority carried high-risk disease features before zanubrutinib-based therapy: 88.9% had an International Prognostic Index (IPI) of 3 or higher; 85.2% exhibited high Ki-67 proliferation (≥80%); and 74.1% had received at least three prior lines of therapy.
The analysis notes broad applicability across subgroups defined by sex, age, and extranodal involvement, with maintained ORR above 70% across these strata.

Therapeutic signal and response dynamics

Across all 27 patients, the overall response rate reached 74.1%, with partial responses comprising 66.7% of patients.
With a median follow-up of about 36.6 months, median PFS was 10.6 months, and median OS was 19.6 months.
Two patients achieved complete response; one proceeded to autologous stem cell transplantation and another to lenalidomide maintenance.
A substantial portion (19 patients) did not achieve CR and were bridged to CAR-T cell therapy; six patients proceeded to additional salvage chemotherapy.

Safety and tolerability

Hematologic toxicities of grade 3 or higher included neutropenia in 85.1% (23/27) and thrombocytopenia in 37% (10/27).
Nonhematologic grade ≥3 adverse events included hypokalemia in 11.1% (3/27) and pulmonary infection in 11.1% (3/27).
Importantly, no treatment-related deaths were reported during the study period.
Overall tolerability was described as manageable within the context of heavily pretreated disease.

CAR-T therapy subgroup findings

In patients bridged to CD19 CAR-T therapy, the observed ORR was 89.5% (95% CI: 67.0%–98.2%), with a CR rate of 57.9% (95% CI: 34.5%–78.9%).
For the CART cohort, median PFS was 14 months (95% CI: 5.2–37.9), and median OS was 27.7 months (95% CI: 10.1–not reached).
Comparative analysis suggested improved OS for the CART group versus non-CART recipients (hazard ratio 0.21, 95% CI: 0.05–0.79; P = 0.02).
Landmark-based evaluation indicated an 80% survival probability at 12 months post-landmark in the CART group, with the non-CART group showing earlier decline, reaching 57.1% at 12 months.

Operational implications and context

The Zanubrutinib-containing regimens demonstrated a tangible clinical activity in a population with high-risk, heavily pretreated non-GCB DLBCL.
The approach appeared to function effectively as a bridging strategy to CAR-T therapy, potentially enhancing subsequent therapeutic opportunities and outcomes.
The safety profile highlighted notable hematologic toxicity but without fatalities attributable to treatment, suggesting manageability within specialized centers.

Limitations and open questions

The study is retrospective and relatively small, limiting causal inference and generalizability.
Heterogeneity in combination regimens and prior therapies may influence outcomes; detailed regimen-specific effects were not delineated.
Prospective validation with larger cohorts is needed to confirm effectiveness, refine safety expectations, and clarify which patient subsets derive the greatest benefit from zanubrutinib-based bridging strategies.

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Frontiers in Immunology