SUMMARY: The FDA on May 15, 2024, granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel) for adults with Relapsed or Refractory Follicular Lymphoma who have received two or more prior lines of systemic therapy. The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).
Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Despite advances in treatment for Follicular Lymphoma, there remains an unmet need for additional options that offer treatment-free intervals with durable, complete responses.
Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the body of patients and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.
Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process, is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody, produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.
BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® contains a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. BREYANZI® was previously approved in the US for the treatment of Relapsed or Refractory Large B-Cell Lymphoma (LBCL) after at least one prior line of therapy, and also received accelerated approval for the treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma after at least two prior lines of therapy.
TRANSCEND-FL is a global, multicenter, open-label, single-arm Phase II trial which included patients with Relapsed or Refractory Follicular Lymphoma after two or more lines of systemic therapy including an anti-CD20 antibody and an alkylating agent. This study included 94 eligible patients (N=94) and these patients also needed to have an ECOG PS of 1 or less, as well as adequate bone marrow function to receive lymphodepleting chemotherapy. Eligible patients had PET-positive disease at baseline or after bridging therapy and had at least 9 months of follow up from first response. Patients were excluded if they had evidence or a history of composite Diffuse Large B-Cell Lymphoma and Follicular Lymphoma, or transformed Follicular Lymphoma, a WHO subclassification of duodenal-type Follicular Lymphoma, CNS-only involvement by malignancy, or prior CAR T-cell therapy or other genetically modified cell therapy. Following apheresis and collection of T cells, patients received lymphodepleting chemotherapy consisting of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV daily for 3 days. Patients could receive bridging therapy for disease control following apheresis and prior to lymphodepletion and subsequent administration of BREYANZI®. Patients received a single dose of BREYANZI® 2-7 days, following the completion of lymphodepleting chemotherapy at a target dose of 100 x 106 CAR-positive T cells.
The Primary efficacy endpoint was the Overall Response Rate (ORR), defined as the percentage of patients achieving a Partial or Complete Response per Lugano criteria as assessed by an Independent Review Committee (IRC). Secondary endpoints included Complete Response (CR) rate, Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and Safety. Responses were evaluated using PET scans, providing a comprehensive assessment of treatment efficacy.
The study demonstrated impressive efficacy outcomes, with an ORR of 95.7% and a CR rate of 73.4% in the primary analysis set. Responses were rapid, with a median time to response of one month. After a median follow up of 16.8 months, the median Duration of Response was Not Reached. Approximately 81% of responders remained in response at 12 months, and 77% of responders remained in response at 18 months, underscoring the potential of this therapy to induce long-lasting remissions. The most common non-laboratory adverse reactions were Cytokine Release Syndrome (CRS), headache, musculoskeletal pain, fatigue, constipation, and fever.
In this largest primary analysis assessing CAR T-cell therapy for Relapsed or Refractory Follicular Lymphoma, a treatment option with a one-time infusion of BREYANZI® with the potential for lasting remission, addresses the unmet need of these patients, heralding a new era in the management of this challenging disease.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma
