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Comparable outcomes with second-line tisa-cel versus standard-of-care for relapsed/refractory aggressive NHL

Dr Michael R. Bishop, David and Etta Jonas Center for Cellular Therapy, University of Chicago, USA
ASH 2021
Phase 3, BELINDA

A late-breaking session at the American Society of Hematology 2021 Annual Meeting featured data that the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (tisa-cel) as second-line treatment did not improve event-free survival (EFS) of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (R/R aNHL) compared to standard-of-care [1]. These results of the phase 3 BELINDA (NCT03570892) study come as a surprise because previous CAR T-cell therapy trials have shown improved clinical outcomes. Understanding the failure of this trial in meeting its primary endpoint is critical for future learnings; the study was published in the New England Journal of Medicine [2].

Patients with aggressive NHLs which are relapsed or refractory within 12 months of first-line treatment have a very poor prognosis [3], Dr Michael R. Bishop (David and Etta Jonas Center for Cellular Therapy, University of Chicago, USA) mentioned at the beginning of his lecture.

Standard-of-care second-line treatment includes platinum-based immunochemotherapy, followed by high-dose chemotherapy and autologous haematopoietic cell transplantation (aHCT) in responsive patients. However, due to inadequate response, more than half of patients will not receive aHCT [4,5].

Tisa-cel, an autologous CAR T-cell therapy targeting CD19, is approved for patients with diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of therapy [6,7]. The question addressed by BELINDA was whether tisa-cell would be better than the current standard-of-care in the second line of treatment.
Same EFS

The BELINDA trial enrolled 322 adults with confirmed R/R aNHL within 12 months after first-line chemo-immunotherapy. All patients underwent leukapheresis for tisa-cel production and were randomized 1:1 to receive tisa-cel (arm A) or standard-of-care (arm B). Patients in arm A could receive bridging therapy, defined as an investigator choice of protocol-defined platinum-based chemotherapy, followed by lymphodepletion and followed by a single tisa-cel infusion. Patients in arm B received investigator choice of platinum-based chemotherapy regimen followed by aHCT in responders or a second platinum-based chemotherapy in non-responders.

The primary endpoint was event-free survival (EFS), defined as death at any time or progressive or stable disease at or after 12 weeks. Median EFS was 3 months in both arms (HR 1.07; 95% CI, 0.82-1.40; P=0.69).

Overall response rate (ORR) at week 12 was 46% in arm A compared to 43% in arm B; complete response rate was 28% in both arms. A higher proportion of patients had PD at week 6, prior to CAR T-cell infusion, in the tisa-cel arm.

These results of the BELINDA trial demonstrated that EFS was not significantly different between tisa-cel and standard-of-care treatment strategies in patients with aNHL that was refractory or relapsed early after first-line treatment. “Our findings suggest the importance of preventing progressive disease (PD) prior to CAR T-cell infusion,” Dr Bishop concluded.

Furthermore, these outcomes may reflect variability in the patient population, timing, and administration of tisa-cel and stem cell transplants, and in the use of chemotherapy. Effective bridging prior to CAR T-cell infusion and a shorter time to infusion for this chemotherapy-refractory patient population could in his view be critical to improve outcomes. “Hopefully, insights from this phase 3 study will help guide optimal use of CAR T cells in patients with R/R aNHL requiring second-line therapy and in the design of future CAR T trials.”

    1. Bishop MR. Tisagenlecleucel Vs Standard of Care As Second-Line Therapy of Primary Refractory or Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma: Analysis of the Phase III Belinda Study. LBA6, ASH 2021 Annual Meeting, 11-14 Dec. 

    2. Bishop MR, et al. N Engl J Med 2022;386(7):629-639.

    3. Costa LJ, et al. Am J Hematol. 2017;92:161-170.

    4. van Imhoff GW, et al. J Clin Oncol. 2017;35:544-551. 

    5. Crump M, et al. J Clin Oncol. 2014;32:3490-6. 

    6. Maude SL, et al. N Engl J Med 2018;378:439-448.

    7. Schuster SJ, et al. N Engl J Med. 2019;380:45-56. 


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