FDA Approves Tisagenlecleucel for Large B-Cell Lymphoma


The FDA has approved tisagenlecleucel (Kymriah) for use in adult patients with relapsed/refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.

Stephen J. Schuster, MD

The FDA has approved tisagenlecleucel (Kymriah) for use in adult patients with relapsed/refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.

The approval is based on the phase II JULIET study, in which the CD19-directed chimeric antigen receptor (CAR) T-cell therapy reached an overall response rate (ORR) of 50% (95% CI, 38%-62%) in adult patients with relapsed/refractory DLBCL.1 The complete response (CR) rate was 32% and the partial response rate was 18%. The median duration of response had not been reached.

"The goal of Kymriah 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," 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, said in a statement.

"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," added Schuster.

Patients in the open-label, multicenter, single-arm trial JULIET were enrolled at 27 study centers in 10 countries on 4 continents. Overall the study enrolled 160 patients with relapsed/refractory DLBCL who had received at least 2 lines of prior chemotherapy, including rituximab and anthracycline, or relapsed following autologous hematopoietic stem cell transplantation (HSCT).

Of the overall population, 106 patients were infused with tisagenlecleucel. The median age was 56 years (range, 22-74) among the 68 patients evaluable for efficacy, with 71% of patients being male and 90% being white.

Seventy-eight percent of patient had DLBCL that was “not otherwise specified,” with 22% having DLBCL following transformation from follicular lymphoma (17% high grade). Prior autologous HSCT had been received by 44% of patients. Patients had received a median number of 3 prior therapies (range, 1-6).

Forty-four percent of patients relapsed after their last therapy and 56% of patients had refractory disease. Ninety percent of patient had been treated with lymphodepleting chemotherapy, including 66% with fludarabine and 24% with bendamustine.

There was a median period of 113 days (range, 47-196) from leukapheresis and cryopreservation to tisagenlecleucel infusion. The median dose in the evaluable patient population was 3.5 × 108 CAR-positive viable T cells (range: 1.0 to 5.2 × 108 cells).

All-grade adverse events occurring in at least 20% of the 106 infused patients included cytokine release syndrome (CRS), infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache. Grade 3/4 infections occurred in 25% of patients and there were cases of grade 3/4 thrombocytopenia (40%) and neutropenia (25%) that lasted more than 28 days.

Severe or life-threatening CRS occurred in 23% of the 106 patients who received tisagenlecleucel. Grade 3/4 neurologic events occurred in 18% of treated patients. These neurologic toxicities were managed with supportive care. Eleven percent of patients experienced severe or life-threatening encephalopathy. Neurological adverse events were not linked to any patient deaths and no cases of cerebral edema led to a patient death.

Tisagenlecleucel is approved through the FDA Risk Evaluation and Mitigation Strategy (REMS) program. According to Novartis, the manufacturer of the CAR T-cell therapy, the REMS program will educate healthcare professionals about the risks that may be associated with the treatment.

In August 2017, tisagenlecleucel became the first CAR T-cell therapy approved by the FDA when the agency authorized the treatment’s use for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

The approval was based on phase II results from the single-arm ELIANA trial. Data from the study published in the New England Journal of Medicine showed that at a median follow-up of 13.1 months, tisagenlecleucel induced an ORR of 81% in children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia ALL.2

In an analysis of 75 infused patients with 3 or more months of follow-up, 60% of patients achieved CR and 21% of patients achieved CR with incomplete blood count recovery following tisagenlecleucel infusion.


  1. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 577.
  2. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018; 378:439-448.
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