Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. Recent advancements include bispecific antibodies, a novel therapeutic approach. These engineered proteins offer a targeted way to fight DLBCL, especially for patients who have not responded to or have relapsed after initial therapies.
Understanding Diffuse Large B-Cell Lymphoma (DLBCL)
DLBCL is the most common aggressive lymphoma, originating from mature B-lymphocytes, a type of white blood cell. It can appear in lymph nodes or in organs outside the lymphatic system. Approximately 25,000 new cases are diagnosed annually in the U.S., often affecting older individuals and being slightly more prevalent in men.
Standard treatments, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), cure many patients. However, some individuals may experience a return of the disease (relapse) or become resistant to initial treatments (refractory).
How Bispecific Antibodies Work
Bispecific antibodies are designed proteins capable of binding to two distinct targets simultaneously. One arm attaches to a specific antigen on cancer cells, such as CD20 or CD19 on lymphoma cells. The other arm binds to an activating protein on an immune effector cell, like CD3 on T-cells.
This dual binding mechanism brings the patient’s own T-cells into close proximity with cancerous B-cells. This engagement activates the T-cells, causing them to proliferate and release cytotoxic substances. The activated T-cells then directly target and destroy tumor cells. This process also triggers the release of pro-inflammatory cytokines, which enhances the anti-tumor immune response.
The design of these antibodies can vary, impacting their interaction with target cells. For instance, some bispecific antibodies are structured with two binding sites for the cancer cell antigen and one for the T-cell antigen, which can enhance binding stability and recognition even on cells with lower antigen expression. This full-length, IgG-like structure also contributes to a more stable molecule with a longer half-life in the body, helping to maintain therapeutic concentrations over time.
Current Bispecific Antibodies for DLBCL
Several bispecific antibodies are approved or in advanced stages of clinical development for treating relapsed or refractory DLBCL. These therapies are considered for patients who have undergone two or more prior lines of systemic therapy.
Glofitamab, marketed as Columvi, is a bispecific antibody approved for relapsed or refractory DLBCL. It binds to CD20 on lymphoma cells and CD3 on T-cells. Glofitamab has a 2:1 configuration, with two CD20-binding sites and one CD3-binding site. This antibody is administered intravenously in a step-up dosage regimen, often with initial doses of 2.5 mg and 10 mg before a flat dose of 30 mg for subsequent cycles. Patients often receive a pre-treatment with obinutuzumab seven days prior to the first glofitamab dose to help mitigate potential side effects.
Epcoritamab, known as Epkinly, is another CD20xCD3 bispecific antibody approved for relapsed or refractory DLBCL and high-grade B-cell lymphoma. Unlike glofitamab, epcoritamab has a 1:1 CD20:CD3 format and is administered subcutaneously, offering a more convenient alternative to intravenous therapies. Patients receive epcoritamab with a cycle 1 step-up dosing schedule, starting with a 0.16 mg priming dose, followed by a 0.8 mg intermediate dose, and then full 48 mg doses. It is administered weekly in cycles 1-3, every two weeks during cycles 4-9, and then every four weeks from cycle 10 onward, until disease progression or unacceptable toxicity.
Managing Treatment and Potential Side Effects
Receiving bispecific antibody treatment involves careful management due to potential side effects, primarily Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). CRS is a systemic inflammatory response triggered by the widespread activation of immune cells and the subsequent release of inflammatory cytokines. Symptoms can include fever, low blood pressure, difficulty breathing, and organ dysfunction, and its onset can occur minutes to hours after infusion.
CRS management often involves close monitoring, particularly with initial doses, which may require hospitalization. Premedications such as corticosteroids (like dexamethasone), antipyretics (like acetaminophen), prehydration, and antihistamines are given before the first few doses to reduce CRS risk and severity. For more severe cases, immunosuppressive therapies like tocilizumab, an anti-IL-6 receptor antibody, may be administered to reverse the syndrome.
ICANS is a neurological toxicity that can occur with bispecific antibody therapies. Symptoms can range from headache and dizziness to confusion, language difficulties, or seizures. Most ICANS events are mild to moderate and resolve without requiring dose reduction or interruption of the antibody.
Management of ICANS involves corticosteroids, such as dexamethasone, due to their ability to penetrate the central nervous system. If dexamethasone alone is not sufficient, other medications like anakinra or anti-epileptic drugs may be considered, especially if there is a risk of seizures. Close collaboration with neurologists and a systems-based approach are important for managing these toxicities to ensure patient safety.