Tisagenlecleucel Not Superior to SOC as 2L Treatment for Aggressive B-cell Lymphoma


Significantly longer event-free survival was not demonstrated with tisagenlecleucel in the second-line setting when compared to standard-of-care second-line therapy in patients with refractory or early relapsed aggressive B-cell lymphoma.

Tisagenlecleucel (Kymriah) in the second-line setting did not result in significantly longer event-free survival (EFS) when compared to standard-of-care (SOC) second-line therapy in patients with refractory or early relapsed aggressive B-cell lymphoma, ultimately missing the primary end point of the phase 3 BELINDA trial (NCT03570892).

In both the tisagenlecleucel and SOC arm, the median EFA was 3.0 months (hazard ratio, 1.07; 95% CI, 0.82-1.40; 2-sided P =.61). The stratified adjusted HR was 0.95 (95% CI, 0.72-1.25).

“There was no difference between tisagenlecleucel saw and the standard of care. The event-free survival on both arms was 3 months using the definition that we defined as part of the study,” said Michael Bishop, MD, professor of medicine and director of Hematopoietic Stem Cell Transplantation Program at The University of Chicago Medicine. “That was the major takeaway, which was surprising and very disappointing, considering that the hypothesis was that T-cell would be significantly superior in terms of event-free survival.”

Second-line treatments are needed for aggressive non-Hodgkin’s lymphomas as patient outcomes are poor for those not responding to or progressing soon after first-line therapy. While an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel, is approved for diffuse large B-cell lymphoma after at least 2 treatment lines, its potential benefits remain unclear to researchers.

The international, open-label, multicenter phase 3 trial enrolled patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. The study was designed to investigate tisagenlecleucel and learn more about its safety and efficacy compared to SOC second-line therapies in adult patients with histologically confirmed, aggressive B-cell non-Hodgkin lymphoma.

To be eligible for enrollment, participants must have been aged 18 or older with histologically confirmed, aggressive B-cell non-Hodgkin lymphoma at relapse or progression after front-line therapy. Relapse or progression within 1 year from the last dose of an anti-CD20 antibody and anthracycline-containing first-line chemoimmunotherapy which had not reached complete response was also needed. Additionally, patients must have had leukapheresis material of non-mobilized cells, a measurable disease on both a CAT and PET scan, and an ECOG status of 0 or 1.

EFS was the primary end point and was measured from the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Secondary end points included local investigator-assessed EFS, overall survival, overall response rate, duration or response, time to response, and more.

Participants on the investigative arm received a single dose of tisagenlecleucel along with the investigator’s choice of optional platinum-based chemoimmunotherapy, followed by lymphodepleting chemotherapy. Within the control arm, participants received SOC. The SOC treatment consisted of investigator’s choice of salvage chemotherapy along with high-dose chemotherapy in responding patients and autologous allogeneic hematopoietic stem cell transplant. Participants in the control arm were allowed to cross over to receive the CAR T-cell product if disease progression was determined by a blinded independent review committee.

Findings concluded that there was no significant difference in regard to median event-free survival between the two groups. The 2 regimens also demonstrated similar responses to therapy at or after week 12 of the study.

The percentage of patients with high-grade lymphomas was shown to be higher in the tisagenlecleucel group than in the SOC group (24.1% vs. 16.9%). The percentage of those with an international prognostic index score of 2 or higher was also higher within the tisagenlecleucel group (65.4% vs. 57.5%).

The median time from the start to tisagenlecleucel infusion was 52 days, and a total of 25.9% of the patients within the tisagenlecleucel group had lymphoma progression at week 6 compared to the SOC group at 13.8%. A response was reported in 46.3% of the patients in the tisagenlecleucel group compared with 42.5% in the SOC group.

The median time to randomization was 92 days (range, 61-158), and median follow-up was 10 months (range, 2.9-23.2). Overall survival data were immature at the data cutoff.

A response occurred in 38.3% of the patients in the tisagenlecleucel group and in 53.8% of those in the SOC group at week 6. Progressive disease was noted in 25.9% and 13.8%, respectively. Additionally, a response occurred at or after the week 12 assessment in 46.3% of the patients a part of the tisagenlecleucel group and in 42.5% of those in the SOC group.

As for safety, grade 3 or higher adverse events attributed to treatment were reported in a large majority of each group. Within the tisagenlecleucel group, 10 patients died from adverse events compared to 13 in the SOC group.

According to the BELINDA investigators, additional studies of tisagenlecleucel are needed to assess which patients may obtain the most benefit from each approach.

“We are hoping that the results from our study can be used to say one should be very aggressive, try to get the CAR T cells in as soon as possible, and that they may need higher doses of lymphodepleting chemotherapy. There potentially may be differences in CAR T cell products for this specific patient population because it is quite successful in other scenarios of aggressive B-cell non-Hodgkin lymphoma. In this more aggressive population, one may have to look at specific car T-cell products,” said Bishop.


1 Bishop MR, Dickinson M, Purtill D et al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022; 386:629-639. doi:10.1056/NEJMoa2116596

2 Tisagenlecleucel in adult patients with aggressive B-cell non-Hodgkin lymphoma (BELINDA). Clinicaltrials.gov. Accessed March 3, 2022. https://clinicaltrials.gov/ct2/show/NCT03570892

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