Treatment Outcomes of Zanubrutinib-Based Regimen in Newly Diagnosed Patients with MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma: A Retrospective Multicenter Real-World Study

Background

Diffuse large B-cell lymphoma (DLBCL) patients with co-expression of MYC (≥40) and BCL2 (≥50%), known as double-expressor lymphoma (DEL), often have poor prognosis with traditional first-line therapies. Zanubrutinib, a Bruton's tyrosine kinase inhibitor, has shown promise in improving treatment outcomes. This study evaluates the efficacy of Zanubrutinib-based regimens in DEL patients.

Aims

This multicenter real-world study aims to assess the efficacy and safety of Zanubrutinib-based regimen in DEL patients.

Methods

This retrospective multicenter real-world study included 46 newly diagnosed DEL patients treated with Zanubrutinib-based regimens. Baseline characteristics, treatment patterns, and real-world outcomes, including best complete response rate (CRR), best overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were collected and analyzed. Univariate analysis was conducted to evaluate the impact of various prognostic factors on treatment outcomes.

Results

A total of 46 patients were included from two medical centers in this study, with 22 patients (47.83%) being male and a median age of 57.8 years. The majority of patients had DEL not otherwise specified (NOS), except for one patient who had transformed from small lymphocytic lymphoma and another who was Epstein-Barr virus-positive. Bulky disease (>5 cm) was present in 9 patients (19.57%), and 17 patients exhibited B symptoms. Extranodal involvement was observed in 84.78% of patients: 15.22% had no extranodal involvement, 54.35% had one extranodal site, and 30.43% had two or more extranodal sites. Only one patient had bone marrow involvement. 21 (45.65%) of patients had elevated lactic dehydrogenase (LDH) levels. According to the Hans algorithm for molecular classification, 36 patients (78.26%) were of the non-germinal center B-cell subtype (non-GCB). Immunohistochemistry revealed that 8 patients (17.39%) were CD5-positive. Regarding treatment regimens, 82.61% (38/46) of patients received a single line of therapy, while 17.39% (8/46) received two or more lines. Autologous stem cell transplantation was performed in 8.70% (4/46) of patients, radiation therapy in 6.52% (3/46), and central nervous system prophylaxis in 10.87% (5/46). The majority of patients (60.87%, 28/46) received R-CHOP or R-CDOP as their chemotherapy regimen, with a smaller proportion receiving more intensive (2.17%, 1/46) or less intensive (17.39%, 8/46) chemotherapy. Additionally, 17.39% (8/46) of patients were treated with lenalidomide, and all patients received Zanubrutinib, with 41.3% (19/46) continuing on Zanubrutinib maintenance therapy.

The best CRR was 73.90% (95% CI, 58.90%-85.70%), and the best ORR was 95.70% (95% CI, 85.20%-99.50%). At a median follow-up of 24 months, the 3-year PFS was 86.27% (95% CI, 75.37%-98.75%), and the 3-year OS was 89.79% (95% CI, 78.40%-100%). Univariate analysis revealed that extranodal involvement, bulky disease, elevated LDH levels, non-GCB subtype, and CD5 positivity did not significantly affect the complete response rate. Additionally, the inclusion of Zanubrutinib overcame the negative prognostic impact of these commonly recognized adverse prognostic factors. Zanubrutinib maintenance therapy showed no difference in PFS compared to non-maintenance therapy (P=0.73). Grade 3/4 adverse events were mainly hematologic toxicities, all manageable, including febrile neutropenia (16.2%), neutropenia (49.2%), anemia (12.3%), and thrombocytopenia (8.2%). No cases of atrial fibrillation, tumor lysis syndrome, or bleeding were reported. No patients discontinued treatment due to toxicity, and there were no treatment-related deaths.

Conclusion

Zanubrutinib-based regimens demonstrated high objective response rates in newly diagnosed DEL patients. Extranodal involvement did not affect the complete response rate, indicating that the addition of Zanubrutinib effectively mitigates negative prognostic factors, such as CD5 positivity. Zanubrutinib maintenance therapy may not be necessary. These findings suggest that Zanubrutinib is a promising component of first-line therapy for this patient population with good tolerability.

No relevant conflicts of interest to declare.

Zanubrutinib is an orally administered small molecule inhibitor of Bruton's tyrosine kinase (BTK). It inhibits BTK activity by forming a covalent bond with the cysteine in the active site of BTK. BTK is a key signaling molecule in the B cell antigen receptor (BCR) and cytokine signaling pathways, involved in the proliferation, trafficking, chemotaxis, and adhesion of B cells, and is widely expressed in various B cell malignancies. Zanubrutinib is primarily used to treat the following diseases in adult patients: Mantle cell lymphoma (MCL) patients who have received at least one prior treatment. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients who have received at least one prior treatment. Adult patients with Waldenström's macroglobulinemia (WM). Patients with relapsed or refractory marginal zone lymphoma (MZL) who have already received at least one course of anti-CD20 based treatment. This study applied a regimen combining Zanubrutinib for double-expressor diffuse large B-cell lymphoma, achieving favorable outcomes and tolerability.