Comparison of CAR-T cell therapy (Axicabtagen-Ciloleucel) with standard immunochemotherapy as first-line treatment in patients with high-risk large B-cell lymphoma

Large B-cell lymphomas (LBCL) are a type of non-Hodgkin lymphoma and affect B lymphocytes, a subtype of white blood cells that are part of the body’s immune system. There are several subtypes of LBCL—the most common being diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma. In these conditions, symptoms may include rapid enlargement of the lymph nodes and involvement of various organs. Patients also frequently report fever, night sweats, and weight loss. The exact cause of LBCL is unknown, but genetic mutations and infections such as the Epstein-Barr virus may play a role. These and various other factors are taken into account in the individual risk assessment for the course of the disease. Risk is classified as low to high. First-line therapy for LBCL often involves a combination of chemotherapy and immunotherapy, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab). The choice of therapy depends, among other factors, on the patient’s overall health and risk assessment. A new form of therapy is treatment with so-called CAR-T cells. In CAR-T cell therapy, the patient’s own immune cells are first harvested. These are then genetically modified so that they can effectively recognize and destroy cancer cells once they are reinfused into the patient via a single infusion. Axicabtagen-Ciloleucel is a form of CAR-T cell therapy that is already approved for the treatment of subtypes of DLBCL when another therapy has already been attempted. Currently, no CAR-T cell therapies are approved for first-line treatment of DLBCL; they are approved only after standard therapies have failed (second-line treatment).

The goal of the ZUMA-23 study (Phase 3 study) is to investigate the efficacy and safety of CAR-T cell therapy with axicabtagen-ciloleucel compared to standard therapy in a larger number of patients. The therapy is administered as first-line treatment, meaning the patients have not received any prior treatment. As part of the study, patients are randomly assigned to two groups. Group 1 first receives a pre-treatment course of chemotherapy (cyclophosphamide + fludarabine) administered as an infusion over 3 days. This is followed by a single administration of the study drug axicabtagen-ciloleucel as an infusion. For patients in Group 2, the medical staff will select one of the two established standard treatments (R-CHOP or DA-EPOCH-R). This treatment is administered over 6 cycles of 21 days each. The study is open-label, meaning that both the medical staff and the patients know which medications are being administered. Follow-up lasts up to 5 years, during which the efficacy of the therapy and the occurrence of side effects from the various medications will be evaluated. The key factor is whether or when the disease progresses again during treatment. The primary endpoint of the study is event-free survival. Five years after randomization, patients from Group 1 will be transferred to a separate long-term study, in which follow-up examinations are planned for an additional 10 years.

Eligible participants are patients aged 18 years or older with LBCL who have received prior treatment consisting of no more than one cycle of rituximab plus chemotherapy. Patients with the following subtypes of large B-cell lymphoma (LBCL) are not eligible to participate in the study: LBCL with a high proportion of T cells or histiocytes (T-cell/histiocyte-rich), primary CNS lymphomas, primary mediastinal (thymic) LBCL, B-cell lymphomas that cannot be clearly classified and exhibit features intermediate between DLBCL and classical Hodgkin lymphoma, Burkitt lymphomas, as well as patients with a so-called Richter transformation in chronic lymphocytic leukemia.