The National Comprehensive Cancer Network (NCCN) guidelines on B-Cell lymphomas (Version 1.2026) include glofitamab plus polatuzumab vedotin as a second-line therapy for Burkitt lymphoma, useful in certain circumstances as a bridge to transplant in patients eligible for allogeneic hematopoietic cell transplantation (HCT). In diffuse large B-cell lymphoma (DLBCL), for patients with relapsed or primary refractory disease who are not candidates for chimeric antigen receptor (CAR) T-cell therapy, preferred second-line options include combinations of gemcitabine and oxaliplatin (GEMOX) with epcoritamab, glofitamab, or polatuzumab vedotin plus rituximab. For classical follicular lymphoma with high tumor burden, recommended first-line therapies include standard chemo-immunotherapy regimens with obinutuzumab or rituximab, and in the second-line extended therapy setting, obinutuzumab maintenance is optional for rituximab-refractory disease. While the guidelines provide disease-specific recommendations for the use of glofitamab, polatuzumab vedotin, and obinutuzumab, they do not discuss the concurrent use of all three agents together for any lymphoma subtype. [1]
A 2025 review on immunotherapy for pediatric DLBCL examined 48 clinical trials investigating relapsed or refractory disease, including studies of immunomodulatory agents, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, checkpoint inhibitors, and CAR T-cell therapy. Bispecific antibodies, including glofitamab, epcoritamab, and odronextamab, have been studied for their ability to facilitate T cell-mediated cytotoxicity against CD20-positive tumor cells. Antibody-drug conjugates, such as zilovertamab vedotin, polatuzumab vedotin, and loncastuximab tesirine, are being evaluated to enhance therapeutic efficacy while minimizing systemic toxicity. Notably, one adult trial combining glofitamab plus polatuzumab with obinutuzumab pretreatment showed high and durable complete remission rates (see Table 1), and pediatric studies are ongoing to assess glofitamab alone or in combination with chemotherapy regimens such as R-ICE. Polatuzumab vedotin, when combined with rituximab and bendamustine, has demonstrated improved complete remission rates in relapsed or refractory DLBCL and is being tested in pediatric populations with reduced-dose chemotherapy. Although obinutuzumab has shown potential cytotoxic benefits over rituximab, data in children remain limited, and ongoing trials are evaluating its use alone or in combination. Overall, while these immunotherapies show promise, the use of glofitamab, polatuzumab vedotin, and obinutuzumab combination therapy in pediatric patients specifically is not discussed within the review. [2]
According to the ClinicalTrials database, the PORTAL trial (NCT06071871) is an ongoing phase 2, open-label study that will evaluate the safety and efficacy of glofitamab, polatuzumab vedotin, and obinutuzumab as a peri-CAR-T cell therapy strategy in patients with relapsed or refractory LBCL. The trial will be conducted in two parts: Part 1 will assess the combination as a bridging therapy to CAR-T cell therapy, and Part 2 will evaluate its efficacy in patients who fail to achieve a complete metabolic response or who progress after CAR-T therapy. Patients in Part 1 will receive two cycles of Pola-Glofit, with obinutuzumab given intravenously at 1 g over 4-5 hours on Cycle 1 Day 1, polatuzumab vedotin at 1.8 mg/kg intravenously over 90 minutes on Cycle 1 Day 2, and glofitamab administered at 2.5 mg intravenously over 4 hours on Cycle 1 Day 8 and 10 mg intravenously over 2 hours on Cycle 1 Day 15, with 24-hour hospitalization after each glofitamab dose. From Cycles 2 to 6, polatuzumab will be given at 1.8 mg/kg intravenously over 30 minutes on Day 1, and glofitamab at 30 mg intravenously over 2 hours on Day 1. Patients not eligible for CAR-T therapy after the initial cycles will have the option to receive up to four additional cycles of Pola-Glofit, followed by six cycles of glofitamab at 30 mg intravenously over 2 hours from Cycles 7 to 12. In Part 2, patients will receive six cycles of Pola-Glofit followed by six cycles of glofitamab, with obinutuzumab administered 7 days prior to the first dose of glofitamab. All cycles in both parts will follow a 21-day schedule, and a step-up dosing regimen will be used. Patients will be closely monitored during infusion and may require hospitalization during the first cycle of glofitamab. Participants will be followed for one year after completion of the final treatment cycle. The study is currently recruiting and is expected to be completed by July 30, 2028. [3]
The clinical trials database also describes a single-arm, multicenter, dose-finding phase 1b/2 study (NCT03533283) evaluating the combination of glofitamab with either atezolizumab or polatuzumab vedotin in adult patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. The study will assess the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D), as well as the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of these combination treatments. An open-label imaging feasibility sub-study will also be conducted to visualize CD8+ T-cells at baseline and following glofitamab treatment, including pre-treatment with obinutuzumab. The trial is currently active, with an estimated completion date of October 16, 2026. Of note, while this study will evaluate these combinations, the use of glofitamab, polatuzumab vedotin, and obinutuzumab together will not be studied. [4]