BELINDA

Incomplete

Bishop MR, et al. "Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma". The New England Journal of Medicine. 2022. 368(7):629-639.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

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) at improving progression-free survival?

Bottom Line

Tisagenlecleucel, an anti-CD19 CAR T-cell therapy, is not superior to standard salvage therapy.

Major Points

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.

Guidelines

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

Design

• Multicenter, double-blind, phase III randomized, controlled trial
• N=322
  • 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.

Population

Inclusion Criteria

• 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

Baseline Characteristics

• 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%

Interventions

• 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.

Outcomes

Comparisons are tisagenlecleucel vs standard-care therapy.

Primary Outcomes

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

Secondary Outcomes

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

Subgroup Analysis

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)

Adverse Events

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)

Criticisms

• 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.

Funding

Supported by Novartis