FDA Grants RMAT Designation to Tisagenlecleucel for Follicular Lymphoma

The FDA has granted a Regenerative Medicine Advanced Therapy designation to tisagenlecleucel for the treatment of patients with relapsed/refractory follicular lymphoma.

The FDA has granted a Regenerative Medicine Advanced Therapy (RMAT) designation to tisagenlecleucel (Kymriah) for the treatment of patients with relapsed/refractory follicular lymphoma, according to Novartis, the manufacturer of the CAR T-cell therapy.

The designation is based on preliminary clinical findings from the multicenter, ongoing phase II ELARA trial, which is exploring tisagenlecleucel in adult patients with relapsed/refractory follicular lymphoma. According to a press release from Novartis, the RMAT program was established under the 21st Century Cures Act to "expedite the development and review of regenerative medicine therapies intended to treat, modify, reverse, or cure a serious condition.”

Commenting on the designation, John Tsai, MD, head of Global Drug Development and chief medical officer, Novartis, stated in the press release, “This designation supports the advancement of Kymriah, which could potentially address an unmet need in certain patients with follicular lymphoma, as we strive to reimagine medicine at Novartis. These patients are often faced with the burden of several years of various treatments as their disease continues to progress.”

The ongoing, single-arm, open-label phase II ELARA trial (NCT03568461) is enrolling patients aged ≥18 years with grade 1, 2, or 3A relapsed/refractory follicular lymphoma. Exclusion criteria include CNS involvement, or receiving prior anti-CD19 therapy, gene therapy, adoptive T-cell therapy, or allogeneic HSCT. The target enrollment is 113 patients. Complete response (CR) rate is the primary end point, with secondary end points including overall response rate (ORR), duration of response, overall survival (OS), cellular kinetics, immunogenicity, safety, and patient-reported outcomes.

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

In 2018, the indication was expanded 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 lines of systemic therapy.

This approval was based on data from the phase II JULIET study, in which tisagenlecleucel reached an ORR of 50% (95% CI, 38%-62%) in adult patients with relapsed/refractory DLBCL.2 The CR rate was 32% and the partial response (PR) rate was 18%; moreover, the median duration of response had not been reached.

Updated results from the JULIET trial presented at the 2018 ASH Annual Meeting confirmed that tisagenlecleucel continued to demonstrate durable ORRs with a median of 19 months of follow-up for patients with relapsed/refractory DLBCL.3

The ORR was 54% (95% CI, 41%-62%) with the CD19-targeted CAR T-cell therapy; the CR rate was 40%, and the remainder of patients had a PR. The median duration of response was not yet reach at the time of the analysis, but 54% of those who initially had a PR had converted to a CR.

At the May 21, 2018, data cutoff, 167 patients were enrolled in the study, of whom 115 had received treatment with a single dose of tisagenlecleucel at a median of 3.0 x 108 CAR-positive T cells. Ninety percent of patients who were enrolled had received bridging therapy and 93% had received lymphodepleting chemotherapy prior to infusion of the CAR T cells. The median time from infusion to data cutoff was 19.3 months.

Moreover, the median age of enrolled patients was 56 years (range, 22-76), and 23% were 65 or older. At baseline, 77% of patients had stage III/IV DLBCL and 17% had double or triple hit disease. More than half of patients (55%) had the germinal center subtype, with 43% having activated B-cell DLBCL. Nearly half of patients (49%) underwent a prior stem cell transplant and 51% had received ≥3 prior therapies.

Additional updated results showed that the 6-month relapse-free survival rate was 66% (95% CI, 51%-78%), which remained consistent at 64% at both the 12- and 18-month data analyses (95% CI, 48%-76%). The median OS for all infused patients was 11.1 months but was not reached for those who achieved a CR to tisagenlecleucel. The 12-month OS rate was 48% (95% Ci, 38%-57%) and the 18-month OS rate was 43% (95% CI, 33%-53%).

Regarding safety, no new deaths were reported since the prior assessment, and adverse events (AEs) remained consistent. Overall, 57% of patients experienced cytokine release syndrome of any grade in the study; 14% had a grade 3 event and 9% had a grade 4 event. The rate of neurological AEs was 20%, with 7% grade 3 and 4% grade 4.

The grading system used for these events likely resulted in an overestimation, as the University of Pennsylvania criteria were used and not the Lee criteria. Further studies are ongoing to uncover the true rates of AEs.

Other AEs of interest included prolonged cytopenias, which occurred in 45% of patients, and infection, which was present in 37% of patients. Additionally, 15% of patients experienced febrile neutropenia and 2% had tumor lysis syndrome.


  1. Novartis Kymriah® receives FDA Regenerative Medicine Advanced Therapy designation in follicular lymphoma. Posted April 22, 2020. https://bit.ly/3cBfT9R. Accessed April 22, 2020.
  2. 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. In: Proceedings from the 2018 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 577.
  3. Schuster SJ, Bishop MR, Tam C, et al. Sustained Disease Control for Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: An Updated Analysis of Juliet, a Global Pivotal Phase 2 Trial of Tisagenlecleucel. In: Proceedings from the 2018 ASH Annual Meeting, December 1-4, 2018; San Diego, CA. Abstract 1684.