In an analysis of the phase III BELINDA trial presented by Bishop et al during the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract LBA-6), the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel was not found to improve event-free survival over the standard of care as a second-line treatment for patients with aggressive non-Hodgkin lymphoma. The results, which come as a surprise after previous CAR T-cell therapy trials have shown improved clinical outcomes, may reflect variability in the patient population, timing, and administration of tisagenlecleucel and stem cell transplants, and in the use of chemotherapy in real-world settings, according to researchers.

Tisagenlecleucel has previously been found to be beneficial as a third-line treatment for patients with aggressive non-Hodgkin lymphoma who typically have an extremely poor prognosis. The new study sought to determine whether tisagenlecleucel could offer benefits earlier in the course of treatment as a second-line therapy before attempting a stem cell transplant.

“We were surprised that event-free survival was identical in both study arms,” said presenting author Michael R. Bishop, MD, of The David and Etta Jonas Center for Cellular Therapy, University of Chicago. “This suggests there is still a lot to be learned about the proper administration of CAR T-cell therapies. As this field progresses, we’re learning that there may be more variables to consider as we seek to optimize CAR T-cell therapies.”

BELINDA Details

The trial enrolled 322 patients with aggressive B-cell non-Hodgkin lymphoma who did not respond to initial chemotherapy or relapsed within 12 months. Patients were randomly assigned to receive tisagenlecleucel or standard of care, which consisted of chemotherapy followed by an autologous stem cell transplant for patients responding to chemotherapy. The majority of patients randomly assigned to receive tisagenlecleucel also received chemotherapy before their CAR T-cell therapy—a treatment strategy known as “bridging”—at their physician’s discretion. At the time of reporting, researchers had tracked patient outcomes for a median of 10 months.

No Difference in Event-Free Survival

The results showed no significant difference between the study arms for the primary endpoint of event-free survival, defined as death at any time or progressive or stable disease at or after 12 weeks. Twenty-eight percent of patients in both study arms showed a complete response to treatment, and the overall response rate was also similar (46% in those receiving tisagenlecleucel vs 43% in those receiving standard of care).

Researchers identified several factors that may have potentially contributed to the current results. As an international trial conducted in 18 countries, researchers observed some real-world variability in the treatment strategies used in different regions and countries. Use of bridging therapy was not uniform, and this led to more patients with progressive disease at infusion, which was associated with a worse outcome. In particular, patients treated in non-U.S. centers tended to receive more cycles of bridging chemotherapy. Time to infusion was also quite variable; overall, patients waited a median of 52 days for their CAR T-cell infusion after leukapheresis, which is relatively long given the aggressive nature of the disease. Time to infusion was shorter in the United States compared with non-U.S. countries. In addition, patients in the standard-of-care arm were allowed to receive up to two different regimens before the strategy was considered a failure. Researchers also noted some potentially meaningful differences between the treatment arms in specific patient groups in terms of disease biology and prognostic factors, and they plan to further analyze the data to understand how these factors may have played a role in the results.

“These findings show the importance of doing randomized trials and comparing their results to help improve outcomes for patients,” said Dr. Bishop. “It gives us tremendous insights into the biology of these very aggressive diseases and points to an opportunity to more closely examine many factors—in particular, the role and timing of bridging therapy.”

About half of patients randomly assigned to receive standard-of-care therapy crossed over to receive tisagenlecleucel, with outcomes similar to those found in previous trials of tisagenlecleucel as a third-line therapy in the same patient population. Both patient groups experienced a relatively high rate of adverse events, but the overall safety profile was consistent with previous studies in this patient population. Fatal adverse events occurred in 10 patients who received tisagenlecleucel and 13 who received standard of care.

The investigators are now performing additional analyses to determine factors that may have affected outcomes in both treatment arms.

Disclosure: The study was funded by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit ash.confex.com.