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Results Encouraging for Glofitamab in CNS Involvement in B-Cell Lymphoma

May 30, 2024

June 2024

Ruth Jessen Hickman, MD

Ruth Jessen Hickman, MD, is a freelance medical and science writer based in Bloomington, Indiana.

The U.S. Food and Drug Administration’s (FDA) recent approvals of the bispecific CD20xCD3 antibodies mosunetuzumab, epcoritamab, and glofitamab have substantially improved prospects for patients with systemic diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, but their utility in treating central nervous system (CNS) lymphoma remains unknown. Although follow-up trials are needed, results of an early case series, published in Blood, suggest that these agents may have utility for CNS lymphomas as well.

Bispecific antibodies such as glofitamab target both CD20 and CD3 by bringing T cells and cancer cells into proximity and activating these T cells to specifically target patients’ tumors. In patients with systemic relapsed or refractory B-cell lymphomas, these agents are associated with response rates between 50% and 80%.

James K. Godfrey, MD, assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope Comprehensive Cancer Center in Duarte, California, said that while physicians have multiple treatment options for CNS lymphomas, the durability of response tends to be poor. For example, the five-year survival rates for patients with primary or secondary CNS lymphoma are only 30 to 40%.

Dr. Godfrey and his colleagues sought to explore the potential role of glofitamab in such patients. They studied four patients with CD20-positive DLBCL and secondary CNS involvement who were treated with glofitamab-based therapy, with the goals of assessing whether glofitamab can cross the blood-brain barrier, redirect T cells to the CNS, and induce clinical response.

Earlier work has demonstrated that the CD20 monoclonal antibody rituximab passes the blood-brain barrier with about 0.1% penetrance, high enough to have some clinical effectiveness as a single agent in CNS lymphoma. Glofitamab, though, is slightly larger than rituximab at roughly 200 kD versus 150 kD, respectively. Using assays in the cerebrospinal fluid (CSF) and peripheral blood, the research team demonstrated that, compared with rituximab, a similar proportion of glofitamab penetrated the CNS (0.1-0.4%).

“The concentrations of glofitamab in the CSF from patients were encouraging, because at least in laboratory and in vitro experiments, they would be sufficient to induce T-cell activation and tumor killing,” Dr. Godfrey said. Moreover, in one patient, immune cell infiltration into the CSF increased after glofitamab treatment, suggesting glofitamab can redirect T cells to CNS lymphomas.

Three of the four patients demonstrated considerable improvement from glofitamab-based treatment. One patient who received glofitamab monotherapy had complete resolution of neurologic symptoms after the first dose, with demonstrable improvement on MRI at two and four months. However, interpretation of response is more challenging for the other patients who improved while also receiving other therapies (e.g., intrathecal chemotherapy).

Two patients experienced transient grade 1-2 cytokine release syndrome (CRS), but none displayed other neurologic side effects from treatment. Dr. Godfrey emphasized that obinutuzumab should be administered a week prior to glofitamab, consistent with current FDA package insert recommendations for glofitamab. He explained that obinutuzumab depletes CD20 targets, which reduces the risk of CRS with glofitamab.

An inherent limitation in the study was its small preliminary nature, which will require follow-up in clinical trials. Dr. Godfrey noted that larger prospective trials will be important to demonstrate efficacy and safety of glofitamab in CNS lymphomas, especially because of concerns of neurotoxicity and potential inflammation in the brain. Dr. Godfrey explained that chimeric antigen receptor-modified T cells approved for patients with secondary CNS lymphomas work similarly to glofitamab without significant risk of neurotoxicity, and he speculated that glofitamab is also likely to be reasonably safe in that respect.

“But that needs to be confirmed and validated in a more rigorous manner in prospective clinical trials,” he said. “Any use of glofitamab for CNS lymphoma outside of a clinical trial would need to proceed with extreme caution given the undefined risk/benefit profile of glofitamab in this situation.”

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Godfrey JK, Gao L, Shouse G, et al. Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma [published online ahead of print, 2024 March 14]. Blood. Doi: 10.1182/blood.2024024168.

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