Zanubrutinib Regimen Findings Support Paradigm Shift in Lymphoma Care

The regimen of zanubrutinib (Brukinsa) plus rituximab (Rituxan) and lenalidomide (Revlimid; ZR2) was safe and efficacious in older patients with de novo diffuse large B-cell lymphoma (DLBCL) while illustrating the effect of T-cell immunological memory on immunotherapy. These findings from the phase 2 trial (NCT04460248) published in Blood suggest that reprogramming the tumor microenvironment toward mechanism-based targeted therapy for aggressive lymphoma may be viable.

Among the overall study population (n = 40), of whom all received at least 1 response assessment in the induction phase, the complete response (CR) rate at the end of induction was 65.0% (95% CI, 48.3%-78.9%). The objective response rate was 75.0% (95% CI, 58.5%-86.8%); 5 patients achieved stable disease, 5 had progressive disease, and 4 achieved a partial response (PR). Of those with a PR, 3 patients had received radiotherapy, and of those 3, 1 achieved a PR after 3 cycles of induction.

With a median follow-up of 34.8 months (range, 6.0-45.3), the 2-year progression-free survival (PFS) and overall survival (OS) rates were 67.1% (95% CI, 50.1%-79.4%) and 82.4% (95% CI, 66.5%-91.2%), respectively. Patients with an International Prognostic Index (IPI) of 0 to 2 had a 2-year PFS rate of 78.6% compared with 61.1% in those with an IPI of 3 to 5 (P = .396); the 2-year OS rates were 92.9% and 76.9%, respectively (P = .250). Those with cell-of-origin germinal B-cell–like (GCB) and non-GCB subtypes had 2-year PFS rates of 76.0% and 60.6%, respectively (P = .321), and 2-year OS rates of 82.4% and 82.6% (P = .936). Those with BCL2 and MYC double expressor (DE) and non-DE subtypes had 2-year PFS rates of 60.6% and 70.0% (P = .565) and 2-year OS rates of 76.9% and 85.0% (P = .575).

Regarding safety, the most common grade 3 or 4 hematologic adverse event (AE) was neutropenia (35.0%); the most common grade 3 or 4 non-hematologic AEs were increased alanine transaminase levels (12.5%), increased aspartate transaminase levels (12.5%), and pulmonary infections (12.5%).

“…This study, based on a promising ‘chemotherapy-free’ regimen that is effective and safe in older patients with de novo DLBCL, provided an improved understanding of the effect of T-cell immunological memory on immunotherapy, and offers a rationale for reprograming the tumor microenvironment as a paradigm shift toward mechanism-based targeted therapy of aggressive lymphoma,” wrote lead study author Peng-Peng Xu, of the Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai Ruijin Hospital of Shanghai Jiao Tong University School of Medicine, with coauthors in the publication.

Forty patients enrolled on the trial. Treatment consisted of oral zanubrutinib at 160 mg twice daily, intravenous rituximab at 375 mg/m² on day 1, and oral lenalidomide at 25 mg on days 2 to 11 from cycles 1 to 6. Those who achieved a CR or PR after induction received oral lenalidomide at 25 mg from days 1 to 10 every 21 days for up to 2 years.

Eligible patients were 75 years or older with de novo DLBCL and had either refused systemic chemotherapy or were unfit/frail for standard chemotherapy. They also had measurable disease lesions of 1.5 cm or more in both the longest and shortest dimensions, as well as more than 3 months of life expectancy.

The median age of patients was 78 years (range, 75-91), 67.5% were male, 70.0% had an ECOG performance status of 0 or 1, 42.5% had cell of origin GCB-like status, and 32.5% had BCL-2/MYC double expression.

The CR rate after 6 cycles or at the end of induction was the primary end point. Secondary end points were OS, PFS, and safety.

Additionally, gene set enrichment analysis, as well as direct comparison of differentially expressed genes, was performed between malignant B cells from the nonresponders and responders. Various immunostimulatory pathways such as antigen presentation, cell adhesion, and interferon gamma signaling were significantly enriched in the responders. Increased expression was observed in HLA-I molecules and HLA-II molecules (P <.05). Immunohistochemistry also showed higher expressions of HLA-I and HLA-II among responders (P = .001 and P = .036, respectively).

An analysis of alterations in the tumor microenvironment was also conducted between responders and nonresponders. There was an increased percentage of conventional type 1 dendritic cells observed among the responders (P = .048). HLA molecules and their transcriptional regulators of HLA-I and HLA-II genes were also increased among responders in a differentially expressed gene analysis.

Twenty infiltrating T-cell and natural killer-cell clusters were observed in all samples following batch correction and unsupervised clustering. Responders had a higher percentage of CD8 effector T cell (Teff)_MCM5 cells (P = .048).

ZR2-induced expanded clones persisted at low abundances when a T-cell receptor sequencing was conducted using peripheral blood mononuclear cell samples from 10 responders with durable remission 3 years following treatment.

Reference

Xu PP, Zhu Y, Shi ZY, et al. A phase 2 study of zanubrutinib in combination with rituximab and lenalidomide in de novo diffuse large B-cell lymphoma. Blood. 2025;146(21):2561-2573. doi:10.1182/blood.2025028649