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In patients with aggressive B-cell Lymphoma who failed first-line treatment, is tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) better than salvage chemotherapy and autologous hematopoietic stem-cell transplantation (standard care group)?
Tisagenlecleucel, an anti-CD19 CAR T-cell therapy, is not superior to standard salvage therapy.
Aggressive non-Hodgkins lymphomas that are refractory to first-line therapy or relapse within the 12 months of therapy carry an extremely poor prognosis. They are quite common too — their annual worldwide incidence is 250,000. The JULIET trial, a multi-center, single-arm, open-label, phase 2 trial showed a response rate of 52% in patients with relapsed or refractory diffuse large B-cell lymphoma receiving tisagenlecleucel; progression-free survival at 24 months was 33%. 
The BELINDA trial is a phase 3, international, randomized trial in patients with aggressive non-Hodgkins lymphoma whose disease is refractory to first-line therapy or relapsed within 12 months. It compared tisagenlecleucel with standard second-line treatments: salvage chemotherapy followed by high-dose chemo and autologous hematopoietic stem cell transplant. This trial did not find tisagenlecleucel to be superior to standard second-line treatment strategies. 
NCCN Guidelines Insights: B-Cell Lymphomas, Version 5.2021
- Second-line and subsequent therapy for DLBCL with intention to proceed to transplant
Preferred regimens (in alphabetical order)
- DHAP (dexamethasone, cisplatin, cytarabine) ‡ rituximab
- DHAX (dexamethasone, cytarabine, oxaliplatin) ‡ rituximab
- GDP (gemcitabine, dexamethasone, cisplatin/carboplatin) ‡ rituximab
- ICE (ifosfamide, carboplatin, etoposide) ‡ rituximab
- Second-line and subsequent therapy for DLBCL for non-candidates for transplant
Preferred regimens (in alphabetical order)
- GemOx ‡ rituximab
- Polatuzumab vedotin ‡ bendamustine ‡ rituximabk,l
- Multicenter, double-blind, phase III randomized, controlled trial
- Tisagenlecleucel group (n=162)
- Standard-care group (n=160)
- Setting: 65 centers in 18 countries
- Enrollment: May 31, 2019 to January 8, 2021 (paused from March 31, 2020 to May 11, 2020 due to COVID-19 pandemic)
- Analysis: Intention-to-treat
- Primary endpoints: Event-free survival (defined as the time from randomization to stable or progressive disease at or after 12 weeks) or death.
- Secondary endpoint: Overall survival (only to be tested if the results for primary end-points were significant), percentage of patients with a response at week 12, safety, and cellular kinetics.
- 18 years of age or older
- Histologically confirmed aggressive B-cell lymphoma
- Lymphoma refractory (no complete response) or relapsed after the receipt of a first-line anti CD20 antibody and anthracycline-containing regimen within 12 months of the last dose
- Eligible for autologous HSCT according to the investigator's assessment
- Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
- Median age (range)- 59.5 years (19-79); 54% were aged more than 65 years
- ECOG performance status of 1: 70.4%
- IPI score of 2 or more: 65.4%
- Disease that was refractory to first-line therapy: 66%
- Relapse within 6 months of first-line therapy: 18.5%
- Relapse 6-12 months after the last dose of first-line therapy: 15.4%
- After obtaining consent, all participants underwent lymphocyte collection via leukapheresis as the trial allowed for crossover from standard-care therapy to adoptive cellular therapy.
- Following leukapheresis, patients underwent randomization in 1:1 ratio with stratification.
- The tisagenlecleucel arm consisted of optional bridging therapy, lymphodepletion chemotherapy (or if contraindicated, bendamustine) followed by a single infusion of 0.6-6x10^8 CAR-positive viable T cells.
- The standard-care treatment arm consisted of investigators' choice of four prespecified chemotherapy regimens ( same as bridging therapy) followed by, in patients showing response, high-dose chemotherapy and autologous HSCT.
- Patients in the standard care arm, if deemed to have an inadequate response on PET-CT on the sixth week could receive a second chemotherapy regimen before HSCT (the aim was to have lowest tumor burden before HSCT).
- Palliative ibrutinib or lenalidomide was used if patients were no longer eligible for HSCT.
- After randomization, patients were followed for response at week 6, week 12, every 3 months for the first year, every 6 months for the second year, and annually for 5 years.
- Efficacy evaluations were done starting at week 12 to allow the time for the full effect of treatment in each group.
Comparisons are tisagenlecleucel vs standard-care therapy.
- Median event-free survival in both groups
- 3.0 months
- Stratified unadjusted hazard ratio for event or death
- 1.07; 95% CI 0.82-1.40; P=0.61
- Overall survival was not tested as there was no significant difference in the primary outcome
- Best overall response at or after week 12
- 46.3% (38.4-54.3) vs. 42.5% (34.7-50.6)
- Saftey (Grade 3 or higher adverse events)
- 84.0% vs 90.0%
- Events considered by the investigators to be treatment-related: 74.7% vs 85.6%
- Cellular Kinetics
- Geometric mean in-vivo peak expansion--2X higher in patients with a response
- Tisagenlecleucel transgene could be detected in 53 (out of 54) samples four months after randomization
- Longer event-free survival was seen in patients with higher-than-median peak expansion
- Patients with high-grade B-cell lymphoma had shorter event-free and overall survival in both treatment groups compared to those with primary mediastinal B-cell lymphoma or diffuse large B-cell lymphoma
- Median event-free survival in non-US countries: 3.3 months vs 3.0 months
- Median event-free survival in the US: 2.9 months vs 3.1 months
- Adjusted hazard ratio for event or death in non-US countries: 0.82 (95% CI, 0.59-1.15)
- Adjusted hazard ratio for event or death in the US: 1.19 (95% CI, 0.64-2.19)
- 61.3% in the Tisagenlecleucel group had cytokine release syndrome (CRS); 5.2% had CRS of grade 3 or higher
- 10.3% in the tisagenlecleucel group had neurologic events; 1.9% of the neurologic events were grade 3 or higher
- Anemia, neutropenia, thrombocytopenia, and nausea were the most common adverse events in both groups
- 32.1% in the tisagenlecleucel and 28.1% in the standard-care group died during the trial (25.9% vs 20% died due to disease progression)
- Multiple differing histologic tumor types were included in the study which could have skewed the overall efficacy of the results.
- The median time from leukapheresis to infusion was 40.5 in the US (and longer in non-US countries). Given the aggressive nature of the disease, faster production times for CAR T-cell therapies are necessary.
Supported by Novartis
- Sehn LH & Salles G Diffuse Large B-Cell Lymphoma. N Engl J Med 2021. 384:842-858.
- Schuster SJ et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2021. 22:1403-1415.
- Bishop MR et al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med 2022. 386:629-639.
- Zelenetz AD et al. NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021. J Natl Compr Canc Netw 2021. 19:1218-1230.