Tisagenlecleucel Yields Durable Responses in R/R Follicular Lymphoma

Patients with relapsed/refractory follicular lymphoma experienced durable responses when treated with tisagenlecleucel (Kymriah) in the phase 2 ELARA study (NCT03568461), according to data presented at the 2023 ASH Annual Meeting.

Data from the study indicated that the median progression-free survival (PFS) was 37 months with a median follow-up of 30 months. Additionally, the 36-month PFS rates in the overall population and those with a complete response (CR) were 53% vs 69%, respectively. Additionally, the median overall survival (OS) among those treated with tisagenlecleucel was not reached, and the 36-month OS rate was 82%.

Investigators reported that neither the duration of response (DOR) nor the time to the next treatment was reached at a median follow-up of 41 months. A total of 54% of all responders (n = 81) maintained a response at the data cutoff. Moreover, the likelihood of remaining in response 33 months following the first response was 63% for CR/partial response (PR) and 73% for CR. Additionally, the likelihood of patients beginning a new treatment at 36 months following tisagenlecleucel was 35% in the efficacy evaluable population (n = 94).

A total of 98 patients were enrolled in the ELARA study and underwent tisagenlecleucel manufacturing with the possibility of bridging therapy with chemotherapy. Following restaging and lymphodepletion in those who received bridging therapy, a total of 97 patients underwent infusion with tisagenlecleucel and 94 were evaluable at the first efficacy assessment at month 3. The study had a median follow-up of 40.6 months (range, 34.2-49.7).

To be included in the study, patients were required to be 18 years of age or older with grade 1 to 3A, relapsed/refractory follicular lymphoma. There also needed to be no evidence of histologic transformation/FL3B or prior treatment with anti-CD19 therapy or allogeneic hematopoietic stem cell transplant.

Tisagenlecleucel was administered via a single intravenous infusion at a dose of 0.6 to 6 x 10⁸ CAR-positive T cells. The study’s primary end point was CR rate by an independent review committee, with key secondary end points including overall response rate, DOR, PFS, OS, safety, and cellular kinetics.

The median patient age was 57 years (range, 29-73). Bulky disease was present in 64% of patients. Additionally, 63% of patients experienced progressive disease at 24 months (POD24) following the first anti-CD20 monoclonal antibody–containing regimen, and 68% were double refractory to an anti-CD20 monoclonal antibody and alkylating agent. Patients also had several comorbidities at baseline, including cardiac disorders (16%), diabetes (10%), and renal insufficiency (8%).

It was reported that rates for PFS and OS at 36 months were consistent for patients who experienced POD24 and those without. Specifically, the 36-month PFS rate was 50.0% (95% CI, 35.8%-61.9%) in those with POD24 and 59.0% (95% CI, 39.5%-73.5%) in those without POD24. The corresponding OS rates in each respective group were 83.0% (95% CI, 69.1%-90.5%) and 80.0% (95% CI, 60.9%-90.6%).

Additionally, it was reported that high baseline levels of peripheral CD8-positive, naïve T cells correlated with long-lasting PFS and DOR.

“[These findings] were consistent with previously reported data from other very early studies in smaller datasets,” according to lead author Stephen J. Schuster, MD, during a presentation on the findings. “Those patients who had a higher concentration of naïve T cells, in particular CD8-positive naïve T cells, were associated with having a prolonged PFS or DOR relative to those who had lower levels.”

Schuster is the director of the lymphoma program and lymphoma translational research, as well as a Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research at Penn Medicine.

Additionally, Schuster emphasized that those who had not experienced POD24 had a higher mean CAR transgene expansion and more durable persistence. Responses and durations did not differ among POD24 subgroups despite expansion differences; CAR transgene persistence was reported up to 1290 days.

Schuster indicated that there were no new findings regarding safety. The most common high-grade toxicities any time after infusion were neutropenia (43%) and anemia (19%), with frequent serious adverse effects (AEs) including cytokine release syndrome (CRS; 20%), pneumonia (11%), and febrile neutropenia (8%).

To date, a total of 18 patients died during the study, with 8 dying due to progressive disease, 9 to AEs, and 1 to euthanasia. AEs resulting in death included metastatic squamous cell carcinoma, encephalitis, pneumonia, bladder transitional cell carcinoma, acute myeloid leukemia, infection, CRS, gastrointestinal hemorrhage, and cardiac arrest.

Reference

Schuster SJ, Fowler N, Dickinson M, et al. Clinical outcomes of patients with relapsed/refractory follicular lymphoma treated with tisagenlecleucel: phase 2 Elara 3-year follow-up. Blood. 2023;142 (suppl 1):601. doi:10.1182/blood-2023-180936