Tisagenlecleucel Safe and Effective in Relapsed/Refractory Follicular Lymphoma

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with tisagenlecleucel (Kymriah) has shown efficacy for the treatment of patients with extensively treated and refractory follicular lymphoma (FL), according to preliminary phase 2 data from the ELARA clinical trial.

For patients with FL, relapse and remission are common occurrences, and there is no curative treatment option available for the disease. Prior to being evaluated in ELARA, tisagenlecleucel achieved durable complete remission (CR) in 71% of patients with relapsed/refractory disease who were part of a 14-patient phase 2a cohort. This trial provided the rationale to explore the use of the drug in a larger population of patients with relapsed/refractory FL.

Ninety-seven patients were assessed on treatment with tisagenlecleucel in ELARA. All patients enrolled were 18 years of age or older with grade 1, 2, or 3A FL. All of the patients had relapsed/refractory disease with no evidence of histological transformation and who received no prior anti-CD19 therapy or allogeneic homologous stem cell transplant. The primary end point was the CR rate assessed by an independent review committee. The secondary end points included the objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety.

Tisagenlecleucel was dosed in the study at 0.6 x 106 CAR-positive viable CAR T cells via single intravenous infusion. Patients also received lymphodepleting chemotherapy of fludarabine 25 mg/m2 given by IV daily for 3 days in combination with IV cyclophosphamide 250 mg/m2 daily for 3 days. Patients who did not receive the chemotherapy combination were given IV bendamustine 90 mg/m2 daily for 2 days. The median dose of tisagenlecleucel infused in patients was 2.06 x 108 CAR-positive viable CAR T cells. Notably, 18% of the study population were treated as outpatients.

The first efficacy assessment in ELARA was conducted at the 3-month mark. In total, 52 patients were evaluable efficacy. At a median follow of 9.9 months (range, 6.0-15.6), the CR rate was 65.3% and the other 17.3% had partial remissions. Later, all but 8 of the PRs were converted to CRs. The conversion occurred between 3 and 6 months in all but one of the patients. The ORR achieved with tisagenlecleucel was 82.7%. Response data slightly differed when evaluated by investigators. Specifically, the investigator-assessed CR rate was 67.3%and the ORR was 88.5%. The ORR was consistent across all patient subgroups, which included the 75.5% of the population who received 2 or more prior therapies, those with more advanced disease, and those who previously underwent allogeneic HSCT.

The median DOR in this analysis was not reached (NR; 95% CI, 8.7-not evaluable [NE]), according to the Kaplan-Meier data. In terms of survival, the median PFS was NR (95% CI, 11-NE), and the median OS was NR (95% CI, NE-NE). It was determined, however, that the 6-month PFS rate was 73.2% (95% CI, 58.2%-83.5%).

Tisagenlecleucel demonstrated a favorable safety profile in this study with no new safety signals observed. Safety was evaluated in all 97 patients and any-grade adverse events (AEs) were observed in 94.8% of the population. More than 73% of the AEs observed were drug-related, but serious AEs were only observed in 38.1% of patients. Grade 3/4 AEs were seen in 70.1% of patients.

Overall, 3 patients in the study died due to AEs. All deaths occurred more than 30 days after infusion with any study drug. Notably, the onset of neurological AEs was 8.5 days (range 40-100), and the median time to onset of cytokine release syndrome (CRS) was 4.0 days (range, 1-14 days).Investigators only observed 1 case of immune effector cell-associated neurotoxicity syndrome within the first 8 weeks of treatment.

In terms of AE of special interest that occurred within 8 weeks of beginning treatment, the most common AEs of any grade were CRS (48.5%), serious neurological AEs, and infection 18.6%. There was also an abundance of hematologic AEs included neutropenia in 28.9% of patients, anemia in 22.75%, and thrombocytopenia in 15.5%. All events of the neurologic toxicity and CRS were resolved after appropriate management.

The primary end point of ELARA was met in August 2020, and these interim data indicate promise for tisagenlecleucel as treatment of patients with relapsed/refractory FL, including those who have undergone 2 or more lines of therapy.

_Reference:

_{Fowler NR, Dickinson M, Dreyling M, et al. Efficacy and safety of tisagenlecleucel in adult patients with relapsed/refractory follicular lymphoma: interim analysis of the phase 2 elara trial. Blood. 2020; 136 (Supple 1): 1–3. doi: 10.1182/blood-2020-138983}