DLBCL Management: Bispecific Antibodies as Emerging Therapeutic Option

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, accounting for approximately 30-40% of all adult non-Hodgkin lymphomas.¹ While a significant proportion of patients achieve cure with frontline chemoimmunotherapy, typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), approximately 30-40% of patients will experience relapsed or refractory disease. For these patients the options narrow quickly and outcomes are poor. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard approach for eligible patients with relapsed DLBCL, but many patients are not candidates due to age, comorbidities, or refractory disease.² The incidence of DLBCL increases with age, with a median age at diagnosis in the mid-60s, which further complicates the eligibility for intensive therapies like ASCT. Patients who relapse after ASCT, or who do not respond to initial salvage, have the worst outlook of all, and they are the population these agents were first tested in.

Bispecific Antibodies in DLBCL: Mechanism and Clinical Context

Bispecific antibodies turn the patient's own T cells against the lymphoma. These engineered immunotherapies simultaneously bind to a CD3 receptor on T-cells and a tumor-associated antigen, such as CD20 or CD19, on lymphoma cells. This dual binding mechanism brings T-cells into close proximity with the malignant B-cells, activating the T-cells to induce direct cytotoxicity against the tumor.³ That is the difference from a conventional monoclonal antibody such as rituximab, which marks the cell for destruction but does not recruit a T cell to do it. The resulting T-cell activation leads to the release of cytotoxic granules and pro-inflammatory cytokines, contributing to a potent anti-tumor effect while aiming to minimize off-target effects compared to traditional chemotherapy.

Clinical investigations have demonstrated the efficacy of several bispecific antibodies in relapsed or refractory DLBCL. Mosunetuzumab, a CD20xCD3 bispecific antibody, showed activity in heavily pretreated patients. A phase 1 dose-escalation study reported a best overall response rate of 34.9% and a complete response rate of 19.4% in patients with aggressive B-cell non-Hodgkin lymphoma, the group that includes DLBCL.⁴ Responses were substantially higher in indolent disease, at 66.2% and 48.5%, so the activity seen in follicular lymphoma does not carry over to DLBCL unchanged.⁴ Another CD20xCD3 bispecific antibody, glofitamab, has also yielded notable results. A phase 1/2 study of glofitamab in relapsed or refractory DLBCL documented an ORR of 51.6% and a CR rate of 39.4%.⁵ These response rates are significant given the advanced disease state and extensive prior treatments, including chemotherapy, rituximab, and in some cases, autologous stem cell transplantation or CAR T-cell therapy, among the enrolled patient populations.

The evidence is thinner than those response rates suggest. The mosunetuzumab data primarily derives from a phase 2 study in follicular lymphoma, with activity in DLBCL noted as "similar," rather than being the primary endpoint or a dedicated DLBCL cohort. Both mosunetuzumab and glofitamab data come from single-arm, open-label studies, meaning there is no direct comparator arm to assess their efficacy against existing standard-of-care treatments for relapsed or refractory DLBCL. These trials focus on objective response rates and complete response rates, which are important, but they are surrogate endpoints. The long-term durability of these responses, progression-free survival, and overall survival benefits require further investigation in larger, potentially randomized, studies. The patient populations in these studies were heavily pretreated, which highlights an unmet need, but it also means the applicability of these agents in earlier lines of therapy or in less heavily pretreated patients remains undefined.

In practice these agents are an option for patients who are not candidates for or have failed high-dose chemotherapy with ASCT, or who have relapsed after CAR T-cell therapy. The administration of these therapies requires careful patient selection and close monitoring for immune-related adverse events, particularly cytokine release syndrome (CRS) and neurological events, often referred to as immune effector cell-associated neurotoxicity syndrome (ICANS).^4,5 CRS can range from mild to severe, manifesting as systemic inflammation, and necessitates prompt recognition and management with established protocols, including corticosteroids or tocilizumab. ICANS also requires immediate intervention. Clinicians should discuss with patients the potential for these toxicities and the need for inpatient monitoring during initial cycles. Future research will clarify the optimal sequencing of bispecific antibodies with other agents, including chemotherapy or other immunotherapies, and identify biomarkers to predict response and guide patient selection, which will be critical for integrating these therapies into broader DLBCL management algorithms.