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Two-thirds of adults with difficult-to-treat follicular lymphoma achieved complete responses following treatment with tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, in a single-arm phase II study.

In the ELARA trial of close to 100 patients with heavily pretreated disease, the overall response rate (ORR) with the autologous anti-CD19 product, called tisa-cel for short, reached 86%, with complete responses seen in 66%, reported Stephen J. Schuster, MD, of the University of Pennsylvania Abramson Cancer Center in Philadelphia.

"These data indicate that tisagenlecleucel's an effective therapy for patients with relapsed or refractory follicular lymphoma, including high-risk subgroups," said Schuster during his presentation at the American Society of Clinical Oncology (ASCO) virtual meeting, with the complete response rate consistent across all prognostically important subgroups.

With a follow-up of about 11 months, median duration of response, progression-free survival (PFS), and overall survival (OS) were not reached. The 6-month PFS rate was 76%.

Half of the patients experienced cytokine release syndrome (CRS), all low grade as defined by the Lee Scale, occurring at a median of 4 days following treatment. In addition, 9.3% of patients reported neurologic toxicities, or immune effector cell-associated neurotoxicity syndrome (ICANS), including one grade ≥3 event.

"Three-quarters of CRS events and 100% of the ICANS events occurred in patients that had bulky disease," noted Schuster, all of which resolved with appropriate management.

"This gives an opportunity to preemptively address those concerns," said ASCO discussant Sonali M. Smith, MD, of the University of Chicago.

Median OS in follicular lymphoma stretches out to 20 years, said Smith, but patients who relapse within 2 years of their initial chemoimmunotherapy have a 5-year survival of just 50%, and responses to therapy tend to decrease with each subsequent line of treatment. This is particularly true for patients with high Follicular Lymphoma International Prognostic Index (FLIPI) scores, she said.

"The vast majority of patients actually do well without aggressive therapies," said Smith, but CAR-T could be appropriate for patients with certain characteristics -- bulky disease, multiple lines of prior treatment, refractory disease, or early progression after initial therapy.

In March, the FDA granted to the CAR-T product axicabtagene ciloleucel (Yescarta) for adults with relapsed or refractory follicular lymphoma following two or more prior regimens, based on results of ZUMA-5.

The follow-up times of 11 to 18.5 months between the two CAR-T products tested in follicular lymphoma are too short "to really make strong recommendations," said Smith.

"It's really unclear if this is a cure," she added. "I think this is a very promising and appropriate option for some patients, but we certainly need more data."

The phase II ELARA trial was an international single-arm trial that enrolled 98 adults with follicular lymphoma who had been exposed to two prior lines of therapy or had failed autologous stem cell transplant.

In all, 97 patients were infused with the CAR-T product (safety cohort) and 94 were evaluable for efficacy. Patients included in the study had grade 1-3A follicular lymphoma and no evidence of histological transformation. Prior anti-CD19 therapy or allogeneic transplant was among the exclusion criteria.

All patients received tisa-cel at a dose of 0.6-6 × 10⁸ CAR-positive viable T cells (median 2.06 × 10⁸) following lymphodepleting chemotherapy with fludarabine plus cyclophosphamide or bendamustine (Bendeka, Treanda), with nearly one-fifth receiving their treatment in an outpatient setting.

Overall, 77.3% of patients experienced adverse events (AEs) thought to be related to treatment, including grade 3/4 AEs in 45.4% and serious AEs in 28.9%. There were three deaths during the trial, with none thought to be related to treatment. No association was seen between dose level and occurrence of CRS or neurologic AEs. CRS events were managed with tocilizumab (Actemra) in 34% of cases and corticosteroids in 6%.

Bridging therapy was allowed following apheresis and used in 44% of patients while tisa-cel was being manufactured. Baseline imaging was repeated prior to infusion for patients who underwent bridging therapy.

Patients enrolled had a median age of 57 (one-fourth were 65 or older), most had an ECOG performance status of 0-1 (96%), about two-thirds had bulky disease at baseline, 85% had stage III/IV disease at study entry, and 60% had a FLIPI score ≥3.

Median number of prior therapies was four, with 28% having been exposed to five previous regimens. Last therapy before relapse was anti-CD20 or alkylating agents in 65%, PI3K inhibitors in 20%, and lenalidomide (Revlimid) and rituximab in 16.5%. Three-fourths of patients were refractory to two or more prior lines of treatment.

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