FDA Expands Tisagenlecleucel Approval to Include Relapsed or Refractory Large B-Cell Lymphoma


On May 1, the U.S. Food and Drug Administration (FDA) approved tisagenlecleucel (Kymriah) suspension for intravenous infusion for the treatment of adult patients with relapsed or refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after two or more lines of systemic therapy. Tisagenlecleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.

Developed by Novartis in collaboration with the University of Pennsylvania, tisagenlecleucel became the first chimeric antigen receptor (CAR) T-cell 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. Tisagenlecleucel 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 and Safety Measures

Tisagenlecleucel is an immunocellular therapy that is a one-time treatment manufactured individually for each patient using the patient’s own T cells. Tisagenlecleucel uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

To ensure all hospitals and their associated clinics are aware of how to manage the risks of cytokine-release syndrome (CRS) and neurologic 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 tisagenlecleucel treatment. To support safe patient access, Novartis has established a network of certified treatment centers throughout the country, where clinicians are trained on the use of tisagenlecleucel and appropriate patient care. These treatment centers are fully operational and prepared to begin treatment of eligible patients with DLBCL.


The FDA approval of tisagenlecleucel in adult patients with relapsed or refractory DLBCL is based on the phase II JULIET clinical trial. JULIET was conducted in collaboration with Penn and is the largest study examining a CAR T-cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the United States, Canada, Australia, Japan, and Europe, including, Austria, France, Germany, Italy, Norway, and the Netherlands. In the JULIET trial, patients were infused in both the inpatient and outpatient settings.

Tisagenlecleucel showed an overall response rate of 50% (95% confidence interval [CI] = 38%–62%), with 32% of patients achieving a complete response and 18% achieving a partial response among 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, as defined by the Penn Grading Scale, occurred in 23%. CRS is a known complication of CAR T-cell therapy that may occur when the engineered cells become activated in the patient's body. The syndrome was managed globally using prior site education on implementation of the CRS treatment algorithm.

Overall, 18% of all infused patients experienced grade 3/4 neurologic events, which were managed with supportive care. Encephalopathy, a distinctive neurotoxicity associated with CAR T-cell therapies, was seen as severe or life-threatening in 11% of patients. There were no deaths attributed to neurologic 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%. The most common (> 20%) adverse events in the JULIET study were CRS, infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.