The FDA has approved tisagenlecleucel suspension for intravenous infusion for its second indication – the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Tisagenlecleucel is not indicated for the treatment of patients with primary central nervous system lymphoma. The treatment, developed in collaboration with the University of Pennsylvania, became the first chimeric antigen receptor T cell (CAR-T) therapy to receive regulatory approval in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is now the only CAR-T cell therapy to receive FDA approval for two distinct indications in non-Hodgkin lymphoma (NHL) and B-cell ALL.
"The goal of [tisagenlecleucel] is to provide physicians with a therapy that has demonstrated durable response rates in relapsed or refractory DLBCL patients, a patient population that has endured multiple rounds of chemotherapy with many having experienced unsuccessful stem cell transplants," said Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in Penn's Perelman School of Medicine and Director of the Lymphoma Program at the Abramson Cancer Center. "With this approval, physicians now have a meaningful therapeutic option that can achieve and maintain a sustained response without stem cell transplant along with a consistent safety profile."
Tisagenlecleucel is an innovative immunocellular therapy that is a one-time treatment manufactured individually for each patient using the patient's own T cells. It uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence. In 2012, Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including tisagenlecleucel, for the investigational treatment of cancers.
To ensure all hospitals and their associated clinics are aware of how to manage the risks of cytokine release syndrome (CRS) and neurological toxicities, tisagenlecleucel is available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate health care professionals about the risks that may be associated with the treatment. To support safe patient access, a network of certified treatment centers throughout the country has been established, which are fully trained on the use of tisagenlecleucel and appropriate patient care, and there are currently treatment centers which are certified and fully operational to begin treatment of eligible patients with DLBCL.
To address the unique aspects of this therapy, various patient programs and resources are available to support safe and timely access for patients and address a range of needs.
JULIET Pivotal Study
The FDA approval of tisagenlecleucel in adult patients with r/r DLBCL is based on the pivotal phase II JULIET clinical trial, the first multi-center global registration study for tisagenlecleucel in adult patients with r/r DLBCL.
JULIET was conducted in collaboration with Penn, and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the U.S., Canada, Australia, Japan, and Europe, including: Austria, France, Germany, Italy, Norway, and the Netherlands. In the JULIET trial, patients were infused in the inpatient and outpatient setting.
Tisagenlecleucel showed an overall response rate (ORR) of 50 percent (95% confidence interval [CI], 38% - 62%), with 32 percent of patients achieving a complete response (CR) and 18 percent achieving a partial response (PR) in 68 patients evaluated for efficacy. The median duration of response was not reached among these patients, indicating sustainability of response.
In all patients infused with tisagenlecleucel (n=106), severe or life-threatening (grade 3/4) CRS, defined by the Penn Grading Scale – a rigorous scale for grading this reaction –, occurred in 23 percent of patients. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient's body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm.
Eighteen percent of all infused patients experienced grade 3/4 neurologic events, which were managed with supportive care. Encephalopathy, a distinctive neurotoxicity associated with CAR-T therapies, was seen as severe or life-threatening in 11 percent of patients. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema have occurred.
Grade 3/4 cytopenias lasting more than 28 days included thrombocytopenia (40%) and neutropenia (25%), and grade 3/4 infections occurred in 25 percent. The most common (>20%) adverse events (AEs) in the JULIET study are CRS, infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache.