Tisagenlecleucel Leads to High CR Rate in Heavily Pretreated, R/R Follicular Lymphoma

Nathan H. Fowler, MD

Tisagenlecleucel (Kymriah) induced a significant number of complete responses (CRs) in patients with relapsed or refractory follicular lymphoma, meeting the primary end point of the phase 2 ELARA trial (NCT03568461) as of the interim analysis of the study.¹

“Preliminary data from this study suggest that tisagenlecleucel is extremely effective in extensively pretreated and refractory patients with relapsed follicular lymphoma,” said Nathan H. Fowler, MD, in a presentation during the 2021 Transplantation & Cellular Therapy Meetings.

Previously, tisagenlecleucel demonstrated a durable complete response (CR) rate of 71% among patients with relapsed or refractory follicular lymphoma in a phase 2a trial. The median progression-free survival (PFS) was 32.4 months, and the median overall survival (OS) was not reached in the follicular lymphoma subgroup.²

ELARA is an international, single-arm, multicenter, open-label study of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory follicular lymphoma.

Patients with grade 1, 2, or 3A follicular lymphoma who had no evidence of histological transformation of stage 3B disease and who had no prior anti-CD19 therapy or an allogeneic stem cell transplantation were eligible for enrollment in the study. Bridging chemotherapy was allowed for patients, but the patient’s disease was reassessed prior to infusion.

Patients underwent apheresis and cryopreservation at the time of screening. Following enrollment, tisagenlecleucel was manufactured and then patients underwent lymphodepletion of fludarabine at 25 mg/m2 intravenously (IV) daily for 3 days and cyclophosphamide at 250 mg/m2 IV daily for 3 days, or 90 mg/m2 IV bendamustine daily for 2 days, followed by infusion of tisagenlecleucel at a range of 0.6 to 6 x 108 CAR-positive viable T cells administered in a single IV infusion.

The primary end point of ELARA was the CR rate as assessed by independent review committee per Lugano 2014 classification, and secondary end points included objective response rate (ORR), duration of response (DOR), PFS, OS, and safety.

As of the interim analysis, 52 of 98 patients were evaluable for efficacy with at least 6 months of follow-up after infusion. Ninety-seven patients were infused and evaluable for safety. The median follow-up for safety was 6.51 months (range, 0.2-15.6) and 9.9 months (range, 6.0-15.6) for efficacy. The median infused dose of tisagenlecleucel was 2.06 x 108 CAR-positive viable T cells. Eighteen percent of patients received their tisagenlecleucel infusion in an outpatient setting.

Among all treated patients, the median age was 57.0 years (range, 29-73), and the majority of patients had an ECOG performance status of 0 (56.7%) prior to infusion, stage III to IV disease at baseline (83.5%), and a Follicular Lymphoma International Prognostic Index (FLIPI) score of at least 3 (59.8%). Patients had received a median of 4 prior therapies (range, 2-13), which included a prior anti-CD20 monoclonal antibody and an alkylating agent in all patients, a PI3K inhibitor in 20.6%, and lenalidomide (Revlimid) and rituximab (Rituxan) in 17.3%. Fowler, of the Department of Lymphoma – Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, commented that this number was quite high, especially for this type of lymphoma.

A total of 59.8% of patients had progressed within 24 months of receiving anti-CD20 monoclonal antibody–containing therapy, 77.3% were refractory to their last therapy, 75.5% were refractory to at least 2 regimens, and 36.1% had undergone a prior autologous hematopoietic stem cell transplant. Bridging therapy was administered in 43.3% of patients, which was most commonly chemoimmunotherapy.

In terms of best overall response, CRs were reported in 65.4% of patients and partial responses in 17.3%, for an ORR of 83.7% by independent central review. The investigator-assessed CR rate was 67.3%. ORR was consistent across subgroups analyzed, which included those with high-risk features and prior stem cell transplant.

The median DOR was not reached (95% CI, 8.7-not evaluable), but the probability of a response lasting at least 6 months was 84.4%. Sixty-nine percent of patients had ongoing responses at the time of data cutoff.

Neither the median PFS nor the median OS were reached at the time of data cutoff. At 6 months, the PFS rate was 73.2% (95% CI, 58.2%-83.5%).

Adverse events (AEs) were observed in 94.8% of all treated patients, 73.2% of which were suspected to be related to treatment with tisagenlecleucel. Serious AEs were reported in 38.1%, which 36.8% being potentially treatment related, grade 3/4 AEs were observed in 70.1% and 38.1% were treatment related. Three deaths were reported on the study, all of which were considered related to progression.

The most common all-grade adverse events occurring any time post infusion were CRS (49.5%), neutropenia (34.0%), anemia (23.7%), headache (22.7%), diarrhea (18.6%), thrombocytopenia (17.5%), white blood cell count decrease (17.5%), and nausea (15.5%).

“The safety profile was quite favorable, especially compared to multiple other products that are in the field,” Fowler said.

AEs of special interest included cytokine release syndrome (all grade, 48.5%; grade ≥3, 0%), serious neurological adverse reactions (CRS; all grade, 9.3%; grade ≥3, 1.0%), infections (all grade, 18.6%; grade ≥3, 4.1%), tumor lysis syndrome (all grade, 1.0%; grade ≥3, 0%), prolonged depletion of B cells/agammaglobulinemia (all grade, 9.3%; grade ≥3, 0%), neutropenia (all grade, 28.9%; grade ≥3, 24.7%), anemia (all grade, 22.7%; grade ≥3, 12.4%), and thrombocytopenia (all grade, 15.5%; grade ≥3, 8.2%).

Neurological events occurred within a median of 8.5 days (range, 4-190) with only 1 case of serious (grade 4) immune effector cell-associated neurotoxicity syndrome (ICANS) reported within the first 8 weeks. These neurological events included encephalopathy (3.1%), ICANS (2.1%), tremor (2.1%), dyskinesia (1.0%), dysphagia (1.0%), muscular weakness (1.0%), and neurotoxicity (1.0%).

CRS was grade 1 in 28.9% of patients and grade 2 in 19.6%. Tocilizumab was administered to treat CRS in 31.9% and corticosteroids in 6.4%. CRS onset was within a median of 4 days (range, 1-14). Four patients were admitted to the ICU for a median of 4 days (range, 2-5).

All neurological and CRS events were resolved with appropriate management.

“I’m happy to say that I think this is a promising therapy for relapsed and refractory follicular lymphoma patients, including patients who have had multiple prior lines of therapy,” Fowler concluded.

_References:

_{1. Fowler NH, 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. Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract 78.}

_{2. Chong EA, Svoboda J, Nasta SD, et al. CD19‐directed car t cell therapy (CTL019) for relapsed/refractory diffuse large b‐cell and follicular lymphomas: four year outcomes. Hematologic Oncol. 2019;37(suppl 2):137-138. doi:10.1002/hon.96_2629}